Neuroactive steroids, compositions, and uses thereof

ABSTRACT

Described herein are neuroactive steroids of the Formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof; wherein R 1 , R 2 , R a , G, X, Y, Z, and n are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. Also provided are pharmaceutical compositions comprising a compound described herein and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.

RELATED APPLICATIONS

The present application is a Continuation of U.S. Ser. No. 15/552,201,filed Aug. 18, 2017, which is a U.S. National Phase Application under 35U.S.C. § 371 of International Application PCT/US2016/018748, filed Feb.19, 2016, which claims priority under 35 U.S.C. § 119(e) to U.S.provisional patent application U.S. Ser. No. 62/118,884, filed Feb. 20,2015. The entire contents of each of the foregoing applications areincorporated herein by reference.

BACKGROUND OF THE INVENTION

Brain excitability is defined as the level of arousal of an animal, acontinuum that ranges from coma to convulsions, and is regulated byvarious neurotransmitters. In general, neurotransmitters are responsiblefor regulating the conductance of ions across neuronal membranes. Atrest, the neuronal membrane possesses a potential (or membrane voltage)of approximately −70 mV, the cell interior being negative with respectto the cell exterior. The potential (voltage) is the result of ion (K⁺,Na⁺, Cl⁻, organic anions) balance across the neuronal semipermeablemembrane. Neurotransmitters are stored in presynaptic vesicles and arereleased under the influence of neuronal action potentials. Whenreleased into the synaptic cleft, an excitatory chemical transmittersuch as acetylcholine will cause membrane depolarization, e.g., a changeof potential from −70 mV to −50 mV. This effect is mediated bypostsynaptic nicotinic receptors which are stimulated by acetylcholineto increase membrane permeability to Na⁺ ions. The reduced membranepotential stimulates neuronal excitability in the form of a postsynapticaction potential.

In the case of the GABA receptor complex (GRC), the effect on brainexcitability is mediated by GABA, a neurotransmitter. GABA has aprofound influence on overall brain excitability because up to 40% ofthe neurons in the brain utilize GABA as a neurotransmitter. GABAregulates the excitability of individual neurons by regulating theconductance of chloride ions across the neuronal membrane. GABAinteracts with its recognition site on the GRC to facilitate the flow ofchloride ions down an electrochemical gradient of the GRC into the cell.An intracellular increase in the levels of this anion causeshyperpolarization of the transmembrane potential, rendering the neuronless susceptible to excitatory inputs, i.e., reduced neuronexcitability. In other words, the higher the chloride ion concentrationin the neuron, the lower the brain excitability and level of arousal.

It is well-documented that the GRC is responsible for the mediation ofanxiety, seizure activity, and sedation. Thus, GABA and drugs that actlike GABA or facilitate the effects of GABA (e.g., the therapeuticallyuseful barbiturates and benzodiazepines (BZs), such as Valium®) producetheir therapeutically useful effects by interacting with specificregulatory sites on the GRC. Accumulated evidence has now indicated thatin addition to the benzodiazepine and barbiturate binding site, the GRCcontains a distinct site for neuroactive steroids. See, e.g., Lan, N. C.et al., Neurochem. Res. (1991) 16:347-356.

Neuroactive steroids can occur endogenously. The most potent endogenousneuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and3α-21-dihydroxy-5-reduced pregnan-20-one, metabolites of hormonalsteroids progesterone and deoxycorticosterone, respectively. The abilityof these steroid metabolites to alter brain excitability was recognizedin 1986 (Majewska, M. D. et al., Science 232:1004-1007 (1986); Harrison,N. L. et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)).

The ovarian hormone progesterone and its metabolites have beendemonstrated to have profound effects on brain excitability (Backstrom,T. et al., Acta Obstet. Gynecol. Scand. Suppl. 130:19-24 (1985); Pfaff,D. W and McEwen, B. S., Science 219:808-814 (1983); Gyermek et al., JMed Chem. 11: 117 (1968); Lambert, J. et al., Trends Pharmacol. Sci.8:224-227 (1987)). The levels of progesterone and its metabolites varywith the phases of the menstrual cycle. It has been well documented thatthe levels of progesterone and its metabolites decrease prior to theonset of menses. The monthly recurrence of certain physical symptomsprior to the onset of menses has also been well documented. Thesesymptoms, which have become associated with premenstrual syndrome (PMS),include stress, anxiety, and migraine headaches (Dalton, K.,Premenstrual Syndrome and Progesterone Therapy, 2nd edition, ChicagoYearbook, Chicago (1984)). Subjects with PMS have a monthly recurrenceof symptoms that are present in premenses and absent in postmenses.

In a similar fashion, a reduction in progesterone has also beentemporally correlated with an increase in seizure frequency in femaleepileptics, i.e., catamenial epilepsy (Laidlaw, J., Lancet, 1235-1237(1956)). A more direct correlation has been observed with a reduction inprogesterone metabolites (Rosciszewska et al., J. Neurol. Neurosurg.Psych. 49:47-51 (1986)). In addition, for subjects with primarygeneralized petit mal epilepsy, the temporal incidence of seizures hasbeen correlated with the incidence of the symptoms of premenstrualsyndrome (Backstrom, T. et al., J. Psychosom. Obstet. Gynaecol. 2:8-20(1983)). The steroid deoxycorticosterone has been found to be effectivein treating subjects with epileptic spells correlated with theirmenstrual cycles (Aird, R. B. and Gordan, G., J. Amer. Med. Soc.145:715-719 (1951)).

A syndrome also related to low progesterone levels is postnataldepression (PND). Immediately after birth, progesterone levels decreasedramatically leading to the onset of PND. The symptoms of PND range frommild depression to psychosis requiring hospitalization. PND is alsoassociated with severe anxiety and irritability. PND-associateddepression is not amenable to treatment by classic antidepressants, andwomen experiencing PND show an increased incidence of PMS (Dalton, K.,Premenstrual Syndrome and Progesterone Therapy, 2nd edition, ChicagoYearbook, Chicago (1984)).

Collectively, these observations imply a crucial role for progesteroneand deoxycorticosterone and more specifically their metabolites in thehomeostatic regulation of brain excitability, which is manifested as anincrease in seizure activity or symptoms associated with catamenialepilepsy, PMS, and PND. The correlation between reduced levels ofprogesterone and the symptoms associated with PMS, PND, and catamenialepilepsy (Backstrom, T. et al., J Psychosom. Obstet. Gynaecol. 2:8-20(1983)); Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2ndedition, Chicago Yearbook, Chicago (1984)) has prompted the use ofprogesterone in their treatment (Mattson et al., “Medroxyprogesteronetherapy of catamenial epilepsy,” in Advances in Epileptology: XVthEpilepsy International Symposium, Raven Press, New York (1984), pp.279-282, and Dalton, K., Premenstrual Syndrome and Progesterone Therapy,2nd edition, Chicago Yearbook, Chicago (1984)). However, progesterone isnot consistently effective in the treatment of the aforementionedsyndromes. For example, no dose-response relationship exists forprogesterone in the treatment of PMS (Maddocks et al., Obstet. Gynecol.154:573-581 (1986); Dennerstein et al., Brit. Med J 290:16-17 (1986)).

New and improved neuroactive steroids are needed that act as modulatingagents for brain excitability, as well as agents for the prevention andtreatment of CNS-related diseases. The compounds, compositions, andmethods described herein are directed toward this end.

SUMMARY OF THE INVENTION

Provided herein are C21-substituted neuroactive steroids designed, forexample, to act as GABA modulators. In certain embodiments, suchcompounds are envisioned to be useful as therapeutic agents for theinducement of anesthesia and/or sedation in a subject. In someembodiments, such compounds are envisioned to be useful as therapeuticagents for treating a CNS-related disorder (e.g., sleep disorder, a mooddisorder, a schizophrenia spectrum disorder, a convulsive disorder, adisorder of memory and/or cognition, a movement disorder, a personalitydisorder, autism spectrum disorder, pain, traumatic brain injury, avascular disease, a substance abuse disorder and/or withdrawal syndrome,or tinnitus) in a subject in need (e.g., a subject with Rett syndrome,Fragile X syndrome, or Angelman syndrome).

In one aspect, provided is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: each X, Y, and Zis independently CH or N; G is —C(R^(3a))(R^(3b))(OR¹); R¹ is C₁-C₆alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl; R² is C₁-C₆ alkyl (e.g., C₁-C₆ haloalkyl), or C₁-C₆ alkoxy;each of R^(3a) and R^(3b) is independently H, D, or C₁-C₆ alkyl; R^(a)is cyano, halogen, nitro, C₁-C₆ alkyl (e.g., C₁-C₆ haloalkyl or C₁-C₆hydroxyalkyl), C₁-C₆ alkoxy (e.g., C₁-C₆ haloalkoxy), S(O)_(m)R^(b),NR^(c)R^(d), C(O)R^(e), or C(O)OR^(f); or two R^(a) groups, togetherwith the atoms to which they are attached, form a 6-membered aryl orheteroaryl ring; R^(b) is C₁-C₆ alkyl, NR^(c)R^(d), or OR^(f); each ofR^(c) and R^(d) is independently H, C₁-C₆ alkyl, C(O)R^(e), orC(O)OR^(f); R^(e) is C₁-C₆ alkyl or NR^(g)R^(h); R^(f)is H or C₁-C₆alkyl; each of R^(g) and R^(h) is independently H or C₁-C₆ alkyl; m is0, 1, or 2; n is 0, 1, 2, 3, or 4; and the compound is not selected froma compound of Table 1.

Also provided herein are pharmaceutical compositions comprising acompound as described herein, e.g., a compound of Formula (I), (I-a),(I-b), (I-c), (II), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), or(III-b), and methods of use and treatment, e.g., such as for inducingsedation and/or anesthesia, for treating a CNS-related disorder.

In another aspect, provided is a pharmaceutical composition comprising acompound as described herein, e.g., a compound of Formula (I), (I-a),(I-b), (I-c), (II), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), or(III-b), and a pharmaceutically acceptable excipient. In certainembodiments, the compound as described herein, e.g., a compound ofFormula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (II-c), (II-d),(II-e), (III-a), or (III-b), is provided in an effective amount in thepharmaceutical composition. In certain embodiments, the compound asdescribed herein, e.g., a compound of Formula (I), (I-a), (I-b), (I-c),(II), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), or (III-b), isprovided in a therapeutically effective amount. In certain embodiments,the compound as described herein, e.g., a compound of Formula (I),(I-a), (I-b), (I-c), (II), (II-a), (II-b), (II-c), (II-d), (II-e),(III-a), or (III-b), is provided in a prophylactically effective amount.

Compounds as described herein, act, in certain embodiments, as GABAmodulators, e.g., effecting the GABA_(A) receptor in either a positiveor negative manner. As modulators of the excitability of the centralnervous system (CNS), as mediated by their ability to modulate GABA_(A)receptor, such compounds are expected to have CNS-activity.

Thus, in another aspect, provided are methods of treating a CNS-relateddisorder in a subject in need thereof, comprising administering to thesubject an effective amount of a compound as described herein, e.g., acompound of Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b),(II-c), (II-d), (II-e), (III-a), or (III-b). In certain embodiments, theCNS-related disorder is selected from the group consisting of a sleepdisorder, a mood disorder, a schizophrenia spectrum disorder, aconvulsive disorder, a disorder of memory and/or cognition, a movementdisorder, a personality disorder, autism spectrum disorder, pain,traumatic brain injury, a vascular disease, a substance abuse disorderand/or withdrawal syndrome, and tinnitus. In certain embodiments, thecompound is administered orally, subcutaneously, intravenously, orintramuscularly. In certain embodiments, the compound is administeredchronically. In certain embodiments, the compound is administeredcontinuously, e.g., by continuous intravenous infusion.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing Detailed Description,Examples, and Claims.

Definitions Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

As used herein a pure enantiomeric compound is substantially free fromother enantiomers or stereoisomers of the compound (i.e., inenantiomeric excess). In other words, an “S” form of the compound issubstantially free from the “R” form of the compound and is, thus, inenantiomeric excess of the “R” form. The term “enantiomerically pure” or“pure enantiomer” denotes that the compound comprises more than 75% byweight, more than 80% by weight, more than 85% by weight, more than 90%by weight, more than 91% by weight, more than 92% by weight, more than93% by weight, more than 94% by weight, more than 95% by weight, morethan 96% by weight, more than 97% by weight, more than 98% by weight,more than 98.5% by weight, more than 99% by weight, more than 99.2% byweight, more than 99.5% by weight, more than 99.6% by weight, more than99.7% by weight, more than 99.8% by weight or more than 99.9% by weight,of the enantiomer. In certain embodiments, the weights are based upontotal weight of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, an enantiomerically pure compoundcan be present with other active or inactive ingredients. For example, apharmaceutical composition comprising enantiomerically pure R-compoundcan comprise, for example, about 90% excipient and about 10%enantiomerically pure R-compound. In certain embodiments, theenantiomerically pure R-compound in such compositions can, for example,comprise, at least about 95% by weight R-compound and at most about 5%by weight S-compound, by total weight of the compound. For example, apharmaceutical composition comprising enantiomerically pure S-compoundcan comprise, for example, about 90% excipient and about 10%enantiomerically pure S-compound. In certain embodiments, theenantiomerically pure S-compound in such compositions can, for example,comprise, at least about 95% by weight S-compound and at most about 5%by weight R-compound, by total weight of the compound. In certainembodiments, the active ingredient can be formulated with little or noexcipient or carrier.

Compound described herein may also comprise one or more isotopicsubstitutions. For example, H may be in any isotopic form, including ¹H,²H (D or deuterium), and ³H (T or tritium); C may be in any isotopicform, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form,including ¹⁶O and ¹⁸O; and the like.

The articles “a” and “an” may be used herein to refer to one or to morethan one (i.e. at least one) of the grammatical objects of the article.By way of example “an analogue” means one analogue or more than oneanalogue.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Insome embodiments, an alkyl group has 1 to 12 carbon atoms (“C₁₋₁₂alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms(“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 6 carbonatoms (“C₁₋₆ alkyl”, also referred to herein as “lower alkyl”). In someembodiments, an alkyl group has 1 to 5 carbon atoms (“C₁₋₅ alkyl”). Insome embodiments, an alkyl group has 1 to 4 carbon atoms (“C₁₋₄ alkyl”).In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C₁₋₃alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms(“C₁₋₂ alkyl”). In some embodiments, an alkyl group has 1 carbon atom(“C₁ alkyl”). In some embodiments, an alkyl group has 2 to 6 carbonatoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groups include methyl (C₁),ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl(C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅), 3-pentanyl (C₅),amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅),and n-hexyl (C₆). Additional examples of alkyl groups include n-heptyl(C₇), n-octyl (C₅) and the like. Unless otherwise specified, eachinstance of an alkyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a“substituted alkyl”) with one or more substituents; e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkyl group is unsubstituted C₁₋₁₀ alkyl (e.g.,—CH₃). In certain embodiments, the alkyl group is substituted C₁₋₁₀alkyl. Common alkyl abbreviations include Me (—CH₃), Et (—CH₂CH₃), iPr(—CH(CH₃)₂), nPr (—CH₂CH₂CH₃), n-Bu (—CH₂CH₂CH₂CH₃), or i-Bu(—CH₂CH(CH₃)₂).

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds, and no triple bonds (“C₂₋₂₀ alkenyl”). Insome embodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms(“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has 2 to 6carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, an alkenyl group has2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In some embodiments, an alkenylgroup has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”). In some embodiments, analkenyl group has 2 to 3 carbon atoms (“C₂₋₃ alkenyl”). In someembodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The oneor more carbon-carbon double bonds can be internal (such as in2-butenyl) or terminal (such as in 1-butenyl). Examples of C₂₋₄ alkenylgroups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl(C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C₂₋₆alkenyl groups include the aforementioned C₂₋₄ alkenyl groups as well aspentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additionalexamples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl(C₈), and the like. Unless otherwise specified, each instance of analkenyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl.In certain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds, and optionally one or more double bonds(“C₂₋₂₀ alkynyl”). In some embodiments, an alkynyl group has 2 to 10carbon atoms (“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl grouphas 2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, analkynyl group has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In someembodiments, an alkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”).In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms(“C₂₋₃ alkynyl”). In some embodiments, an alkynyl group has 2 carbonatoms (“C₂ alkynyl”). The one or more carbon-carbon triple bonds can beinternal (such as in 2-butynyl) or terminal (such as in 1-butynyl).Examples of C₂₋₄ alkynyl groups include, without limitation, ethynyl(C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄),and the like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₅), and the like. Unless otherwise specified, each instance of analkynyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted alkynyl”) or substituted (a“substituted alkynyl”) with one or more substituents; e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 πelectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Arylgroups include, but are not limited to, phenyl, naphthyl, indenyl, andtetrahydronaphthyl. Unless otherwise specified, each instance of an arylgroup is independently optionally substituted, i.e., unsubstituted (an“unsubstituted aryl”) or substituted (a “substituted aryl”) with one ormore substituents. In certain embodiments, the aryl group isunsubstituted C₆₋₁₄ aryl. In certain embodiments, the aryl group issubstituted C₆₋₁₄ aryl.

In certain embodiments, an aryl group substituted with one or more ofgroups selected from halo, C₁-C₈ alkyl, C₁-C₈ haloalkyl, cyano, hydroxy,C₁-C₈ alkoxy, and amino.

Examples of representative substituted aryls include the following

wherein one of R⁵⁶ and R⁵⁷ may be hydrogen and at least one of R⁵⁶ andR⁵⁷ is each independently selected from C₁-C₈ alkyl, C₁-C₈ haloalkyl,4-10 membered heterocyclyl, alkanoyl, C₁-C₈ alkoxy, heteroaryloxy,alkylamino, arylamino, heteroarylamino, NR⁵⁸COR⁵⁹, NR⁵⁸SOR⁵⁹NR⁵⁸SO₂R⁵⁹,COOalkyl, COOaryl, CONR⁵⁸R⁵⁹, CONR⁵⁸OR⁵⁹, NR⁵⁸R⁵⁹, SO₂NR⁵⁸R⁵⁹, S-alkyl,SOalkyl, SO₂alkyl, Saryl, SOaryl, SO₂aryl; or R⁵⁶ and R⁵⁷ may be joinedto form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms,optionally containing one or more heteroatoms selected from the group N,O, or S. R⁶⁰ and R⁶¹ are independently hydrogen, C₁-C₈ alkyl, C₁-C₄haloalkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,substituted C₆-C₁₀ aryl, 5-10 membered heteroaryl, or substituted 5-10membered heteroaryl.

Other representative aryl groups having a fused heterocyclyl groupinclude the following:

wherein each W is selected from C(R⁶⁶)₂, NR⁶⁶, O, and S; and each Y isselected from carbonyl, NR⁶⁶, O and S; and R⁶⁶ is independentlyhydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl,C₆-C₁₀ aryl, and 5-10 membered heteroaryl.

“Halo” or “halogen,” independently or as part of another substituent,mean, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine(Br), or iodine (I) atom. The term “halide” by itself or as part ofanother substituent, refers to a fluoride, chloride, bromide, or iodideatom. In certain embodiments, the halo group is either fluorine orchlorine.

“Haloalkyl” and “haloalkoxy” can include alkyl and alkoxy structuresthat are substituted with one or more halo groups or with combinationsthereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” includehaloalkyl and haloalkoxy groups, respectively, in which the halo isfluorine.

“Hydroxy” or “hydroxyl,” independently or as part of anothersubstituent, mean, unless otherwise stated, a —OH group.

Hydroxyalkyl” or “hydroxylalkyl” can include alkyl structures that aresubstituted with one or more hydroxyl groups.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following formulae:

wherein each Y is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ isindependently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, and 5-10 membered heteroaryl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is a substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅-6 cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged or spiro ring systemsuch as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

Particular examples of heterocyclyl groups are shown in the followingillustrative examples:

wherein each W is selected from CR⁶⁷, C(R⁶⁷)₂, NR⁶⁷, O, and S; and eachY is selected from NR⁶⁷, O, and S; and R⁶⁷ is independently hydrogen,C₁-C₈alkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,and 5-10-membered heteroaryl. These heterocyclyl rings may be optionallysubstituted with one or more groups selected from the group consistingof acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (e.g.,amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro,thiol, —S-alkyl, —S-aryl, —S(O)-alkyl, —S(O)-aryl, —S(O)₂-alkyl, and—S(O)₂-aryl. Substituting groups include carbonyl or thiocarbonyl whichprovide, for example, lactam and urea derivatives.

“Acyl” refers to a radical —C(O)R²⁰, where R²⁰ is hydrogen, substitutedor unsubstitued alkyl, substituted or unsubstitued alkenyl, substitutedor unsubstitued alkynyl, substituted or unsubstitued carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstitued heteroaryl, as defined herein.“Alkanoyl” is an acyl group wherein R²⁰ is a group other than hydrogen.Representative acyl groups include, but are not limited to, formyl(—CHO), acetyl (—C(═O)CH₃), cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl (—C(═O)Ph), benzylcarbonyl(—C(═O)CH₂Ph), —C(O)—C₁-C₈ alkyl, —C(O)—(CH₂)_(t)(C₆-C₁₀ aryl),—C(O)—(CH₂)_(t)(5-10 membered heteroaryl), —C(O)—(CH₂)_(t)(C₃-C₁₀cycloalkyl), and —C(O)—(CH₂)_(t)(4-10 membered heterocyclyl), wherein tis an integer from 0 to 4. In certain embodiments, R²¹ is C₁-C₈ alkyl,substituted with halo or hydroxy; or C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, arylalkyl, 5-10 membered heteroaryl orheteroarylalkyl, each of which is substituted with unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy.

“Acylamino” refers to a radical —NR²²C(O)R²³, where each instance of R²²and R²³ is independently hydrogen, substituted or unsubstitued alkyl,substituted or unsubstitued alkenyl, substituted or unsubstituedalkynyl, substituted or unsubstitued carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstitued heteroaryl, as defined herein, or R²² is anamino protecting group. Exemplary “acylamino” groups include, but arenot limited to, formylamino, acetylamino, cyclohexylcarbonylamino,cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino.Particular exemplary “acylamino” groups are —NR²⁴C(O)—C₁-C₈ alkyl,—NR²⁴C(O)—(CH₂)_(t)(C₆-C₁₀ aryl), —NR²⁴C(O)—(CH₂)_(t)(5-10 memberedheteroaryl), —NR²⁴C(O)—(CH₂)_(t)(C₃-C₁ cycloalkyl), and—NR²⁴C(O)—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integerfrom 0 to 4, and each R²⁴ independently represents hydrogen or C₁-C₈alkyl. In certain embodiments, R²⁵ is H, C₁-C₈ alkyl, substituted withhalo or hydroxy; C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each ofwhich is substituted with unsubstituted C₁-C₄ alkyl, halo, unsubstitutedC₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy or hydroxy; and R²⁶ isH, C₁-C₈ alkyl, substituted with halo or hydroxy; C₃-C₁₀ cycloalkyl,4-10-membered heterocyclyl, C₆-C₁₀ aryl, arylalkyl, 5-10-memberedheteroaryl or heteroarylalkyl, each of which is substituted withunsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄ alkoxy,unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl, orunsubstituted C₁-C₄ haloalkoxy or hydroxy; provided at least one of R²⁵and R²⁶ is other than H.

“Acyloxy” refers to a radical —OC(O)R²⁷, where R²⁷ is hydrogen,substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl,substituted or unsubstitued alkynyl, substituted or unsubstituedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstitued heteroaryl, asdefined herein. Representative examples include, but are not limited to,formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl,and benzylcarbonyl. In certain embodiments, R²⁸ is C₁-C₈ alkyl,substituted with halo or hydroxy; C₃-C₁₀ cycloalkyl, 4-10-memberedheterocyclyl, C₆-C₁₀ aryl, arylalkyl, 5-10-membered heteroaryl orheteroarylalkyl, each of which is substituted with unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy.

“Alkoxy” refers to the group —OR²⁹ where R²⁹ is substituted orunsubstituted alkyl, substituted or unsubstitued alkenyl, substituted orunsubstitued alkynyl, substituted or unsubstitued carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstitued heteroaryl. Particular alkoxygroups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.Particular alkoxy groups are lower alkoxy, i.e., with between 1 and 6carbon atoms. Further particular alkoxy groups have between 1 and 4carbon atoms.

In certain embodiments, R²⁹ is a group that has 1 or more substituents,for instance from 1 to 5 substituents, and particularly from 1 to 3substituents, in particular 1 substituent, selected from the groupconsisting of amino, substituted amino, C₆-C₁₀ aryl, aryloxy, carboxyl,cyano, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10membered heteroaryl, hydroxy, nitro, thioalkoxy, thioaryloxy, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—. Exemplary“substituted alkoxy” groups include, but are not limited to,—O—(CH₂)_(t)(C₆-C₁₀ aryl), —O—(CH₂)_(t)(5-10 membered heteroaryl),—O—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and —O—(CH₂)_(t)(4-10 memberedheterocyclyl), wherein t is an integer from 0 to 4 and any aryl,heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves besubstituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy. Particular exemplary‘substituted alkoxy’ groups are —OCF₃, —OCH₂CF₃, —OCH₂Ph,—OCH₂-cyclopropyl, —OCH₂CH₂OH, and —OCH₂CH₂NMe₂.

“Amino” refers to the radical —NH₂.

“Substituted amino” refers to an amino group of the formula —N(R³⁸)₂wherein R³⁸ is hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstitued alkenyl, substituted or unsubstitued alkynyl,substituted or unsubstitued carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstitued heteroaryl, or an amino protecting group, wherein at leastone of R³⁸ is not a hydrogen. In certain embodiments, each R³⁸ isindependently selected from hydrogen, C₁-C₈ alkyl, C₃-C₈ alkenyl, C₃-C₈alkynyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl, 4-10 memberedheterocyclyl, or C₃-C₁₀ cycloalkyl; or C₁-C₈ alkyl, substituted withhalo or hydroxy; C₃-C₈ alkenyl, substituted with halo or hydroxy; C₃-C₈alkynyl, substituted with halo or hydroxy, or —(CH₂)_(t)(C₆-C₁₀ aryl),—(CH₂)_(t)(5-10 membered heteroaryl), —(CH₂)_(t)(C₃-C₁₀ cycloalkyl), or—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integer between0 and 8, each of which is substituted by unsubstituted C₁-C₄ alkyl,halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy; or both R³⁸ groups are joined to form an alkylene group.

Exemplary “substituted amino” groups include, but are not limited to,—NR³⁹—C₁-C₈ alkyl, —NR³⁹—(CH₂)_(t)(C₆-C₁₀ aryl), —NR³⁹—(CH₂)_(t)(5-10membered heteroaryl), —NR³⁹ (CH₂)_(t)(C₃-C₁₀ cycloalkyl), and—NR³⁹—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integerfrom 0 to 4, for instance 1 or 2, each R³⁹ independently representshydrogen or C₁-C₈ alkyl; and any alkyl groups present, may themselves besubstituted by halo, substituted or unsubstituted amino, or hydroxy; andany aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, maythemselves be substituted by unsubstituted C₁-C₄ alkyl, halo,unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstitutedC₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄haloalkoxy or hydroxy. For theavoidance of doubt the term ‘substituted amino’ includes the groupsalkylamino, substituted alkylamino, alkylarylamino, substitutedalkylarylamino, arylamino, substituted arylamino, dialkylamino, andsubstituted dialkylamino as defined below. Substituted amino encompassesboth monosubstituted amino and disubstituted amino groups.

“Azido” refers to the radical —N₃.

“Carbamoyl” or “amido” refers to the radical —C(O)NH₂.

“Substituted carbamoyl” or “substituted amido” refers to the radical—C(O)N(R⁶²)₂ wherein each R⁶² is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstitued alkenyl, substituted orunsubstitued alkynyl, substituted or unsubstitued carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstitued heteroaryl, or an amino protectinggroup, wherein at least one of R⁶² is not a hydrogen. In certainembodiments, R⁶² is selected from H, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl,4-10 membered heterocyclyl, C₆-C₁₀ aryl, and 5-10 membered heteroaryl;or C₁-C₈ alkyl substituted with halo or hydroxy; or C₃-C₁₀ cycloalkyl,4-10 membered heterocyclyl, C₆-C₁₀ aryl, or 5-10 membered heteroaryl,each of which is substituted by unsubstituted C₁-C₄ alkyl, halo,unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstitutedC₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy or hydroxy;provided that at least one R⁶² is other than H.

“Carboxy” refers to the radical —C(O)OH.

“Cyano” refers to the radical —CN.

“Nitro” refers to the radical —NO₂.

“Ethenyl” refers to substituted or unsubstituted —(C═C)—. “Ethylene”refers to substituted or unsubstituted —(C—C)—. “Ethynyl” refers to—(C≡C)—.

“Nitrogen-containing heterocyclyl” group means a 4- to 7-memberednon-aromatic cyclic group containing at least one nitrogen atom, forexample, but without limitation, morpholine, piperidine (e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline,imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methyl piperazine. Particular examples includeazetidine, piperidone and piperazone.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that results in theformation of a stable compound. The present invention contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this invention, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃+X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆-14 aryl, and5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(aa) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R, —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆-14 aryl, and5-14 membered heteroaryl, or two R^(bb) groups are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee),—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; wherein X is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, and the like).

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quarternary nitrogenatoms. Exemplary nitrogen atom substitutents include, but are notlimited to, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(aa), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14-memberedheteroaryl, or two R^(cc) groups attached to a nitrogen atom are joinedto form a 3-14-membered heterocyclyl or 5-14-membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined above.

In certain embodiments, the substituent present on a nitrogen atom is anamino protecting group (also referred to herein as a nitrogen protectinggroup). Amino protecting groups include, but are not limited to, —OH,—OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)OR^(aa), —C(═O)N(R^(cc))₂,—S(═O)₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14-memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14-membered heteroaryl groups, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd)groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are as definedherein. Amino protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

Exemplary amino protecting groups include, but are not limited to amidegroups (e.g., —C(═O)R^(aa)), which include, but are not limited to,formamide and acetamide; carbamate groups (e.g., —C(═O)OR^(aa)), whichinclude, but are not limited to, 9-fluorenylmethyl carbamate (Fmoc),t-butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups(e.g., —S(═O)₂R^(aa)), which include, but are not limited to,p-toluenesulfonamide (Ts), methanesulfonamide (Ms), andN-[2-(trimethylsilyl)ethoxy]methylamine (SEM).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to as a hydroxyl protectinggroup). Oxygen protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and —P(═O)(NR^(bb))₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn),triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS),t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), andtosylate (Ts).

In certain embodiments, the substituent present on an sulfur atom is ansulfur protecting group (also referred to as a thiol protecting group).Sulfur protecting groups include, but are not limited to, —R^(aa),—N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R, —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃,—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and—P(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein. Sulfur protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and Claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

Other Definitions

As used herein, the term “modulation” refers to the inhibition orpotentiation of GABA receptor function. A “modulator” (e.g., a modulatorcompound) may be, for example, an agonist, partial agonist, antagonist,or partial antagonist of the GABA receptor.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, and more particularly, in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non-toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like. The term“pharmaceutically acceptable cation” refers to an acceptable cationiccounter-ion of an acidic functional group. Such cations are exemplifiedby sodium, potassium, calcium, magnesium, ammonium, tetraalkylammoniumcations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977)66(1): 1-79.

“Solvate” refers to forms of the compound that are associated with asolvent or water (also referred to as “hydrate”), usually by asolvolysis reaction. This physical association includes hydrogenbonding. Conventional solvents include water, ethanol, acetic acid, andthe like. The compounds of the invention may be prepared e.g. incrystalline form and may be solvated or hydrated. Suitable solvatesinclude pharmaceutically acceptable solvates, such as hydrates, andfurther include both stoichiometric solvates and non-stoichiometricsolvates. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Representative solvates includehydrates, ethanolates and methanolates.

As used herein, the term “isotopic variant” refers to a compound thatcontains unnatural proportions of isotopes at one or more of the atomsthat constitute such compound. For example, an “isotopic variant” of acompound can contain one or more non-radioactive isotopes, such as forexample, deuterium (²H or D), carbon-13 (¹³C), nitrogen-15 (¹⁵N), or thelike. It will be understood that, in a compound where such isotopicsubstitution is made, the following atoms, where present, may vary, sothat for example, any hydrogen may be ²H/D, any carbon may be ¹³C, orany nitrogen may be ¹⁵N, and that the presence and placement of suchatoms may be determined within the skill of the art. Likewise, theinvention may include the preparation of isotopic variants withradioisotopes, in the instance for example, where the resultingcompounds may be used for drug and/or substrate tissue distributionstudies. The radioactive isotopes tritium, i.e., ³H, and carbon-14,i.e., ¹⁴C, are particularly useful for this purpose in view of theirease of incorporation and ready means of detection. Further, compoundsmay be prepared that are substituted with positron emitting isotopes,such as ¹¹C, ¹⁸F, ¹⁵O, and ¹³N, and would be useful in Positron EmissionTopography (PET) studies for examining substrate receptor occupancy. Allisotopic variants of the compounds provided herein, radioactive or not,are intended to be encompassed within the scope of the invention.

“Stereoisomers”: It is also to be understood that compounds that havethe same molecular formula but differ in the nature or sequence ofbonding of their atoms or the arrangement of their atoms in space aretermed “isomers.” Isomers that differ in the arrangement of their atomsin space are termed “stereoisomers.” Stereoisomers that are not mirrorimages of one another are termed “diastereomers” and those that arenon-superimposable mirror images of each other are termed “enantiomers.”When a compound has an asymmetric center, for example, it is bonded tofour different groups, a pair of enantiomers is possible. An enantiomercan be characterized by the absolute configuration of its asymmetriccenter and is described by the R- and S-sequencing rules of Cahn andPrelog, or by the manner in which the molecule rotates the plane ofpolarized light and designated as dextrorotatory or levorotatory (i.e.,as (+) or (−)-isomers respectively). A chiral compound can exist aseither individual enantiomer or as a mixture thereof. A mixturecontaining equal proportions of the enantiomers is called a “racemicmixture”.

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of it electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenylnitromethane, that arelikewise formed by treatment with acid or base. Tautomeric forms may berelevant to the attainment of the optimal chemical reactivity andbiological activity of a compound of interest.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or anon-human animal, e.g., a mammal such as primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents,cats, and/or dogs. In certain embodiments, the subject is a human. Incertain embodiments, the subject is a non-human animal. The terms“human,” “patient,” and “subject” are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the specified disease, disorderor condition (“prophylactic treatment”).

In general, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response, e.g., to treat aCNS-related disorder, is sufficient to induce anesthesia or sedation. Aswill be appreciated by those of ordinary skill in this art, theeffective amount of a compound of the invention may vary depending onsuch factors as the desired biological endpoint, the pharmacokinetics ofthe compound, the disease being treated, the mode of administration, andthe age, weight, health, and condition of the subject. An effectiveamount encompasses therapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease, disorder or condition, or one or more symptoms associated withthe disease, disorder or condition, or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease,disorder or condition. The term “prophylactically effective amount” canencompass an amount that improves overall prophylaxis or enhances theprophylactic efficacy of another prophylactic agent.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS THE INVENTION

As generally described herein, provided herein are C21-substitutedneuroactive steroids designed, for example, to act as GABA modulators.In certain embodiments, such compounds are envisioned to be useful astherapeutic agents for the inducement of anesthesia and/or sedation in asubject. In certain embodiments, such compounds are envisioned to beuseful as therapeutic agents for treating a CNS-related disorder.

Compounds

In one aspect, provided is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: each X, Y, and Zis independently CH or N; G is-C(R^(3a))(R^(3b))(OR¹); R¹ is C₁-C₆alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl; R² is C₁-C₆ alkyl (e.g., C₁-C₆ haloalkyl), or C₁-C₆ alkoxy;each of R^(3a) and R^(3b) is independently H, D, or C₁-C₆ alkyl; R^(aa)is cyano, halogen, nitro, C₁-C₆ alkyl (e.g., C₁-C₆ haloalkyl or C₁-C₆hydroxyalkyl), C₁-C₆ alkoxy (e.g., C₁-C₆ haloalkoxy), S(O)_(m)R^(b),NR^(c)R^(d), C(O)R^(e), or C(O)OR^(f); or two R^(aa) groups, togetherwith the atoms to which they are attached, form a 6-membered aryl orheteroaryl ring; R^(b) is C₁-C₆ alkyl, NR^(c)R^(d), or OR^(f); each ofR^(c) and R^(d) is independently H, C₁-C₆ alkyl, C(O)R^(e), orC(O)OR^(f); R^(e) is C₁-C₆ alkyl or NR^(g)R^(h); R^(f) is H or C₁-C₆alkyl; each of R^(g) and R^(h) is independently H or C₁-C₆ alkyl; m is0, 1, or 2; and n is 0, 1, 2, 3, or 4.

In some embodiments, the compound is not selected from a compound ofTable 1.

In some embodiments, X is N. In some embodiments, X is N, and Y and Zare CH.

In some embodiments, Y and Z are CH.

In some embodiments, Y is N. In some embodiments, Y is N, and X and Zare CH.

In some embodiments, Z is N. In some embodiments, X and Z are N, and Yis CH. In some embodiments, X, Y, and Z are N.

In some embodiments, R¹ is C₁-C₆ alkyl. In some embodiments, R¹ is —CH₃,—CH₂CH₃, or —CH(CH₃)₂. In some embodiments, R¹ is —CH₃. In someembodiments, R¹ is —CH₂CH₃. In some embodiments, R¹ is —CH(CH₃)₂.

In some embodiments, R² is C₁-C₆ alkyl. In some embodiments, R² is —CH₃.

In some embodiments, R² is C₁-C₆ haloalkyl. In some embodiments, R² is—CF₃.

In some embodiments, each of R^(3a) and R^(3b) is independently H or D.In some embodiments, each of R^(3a) and R^(3b) is independently H. Insome embodiments, each of R^(3a) and R^(3b) is independently D. In someembodiments, one of R^(3a) and R^(3b) is H, D, or C₁-C₆ alkyl (e.g.,CH₃), and the other of R^(3a) and R^(3b) is H. In some embodiments, oneof R^(3a) and R^(3b) is D or C₁-C₆ alkyl (e.g., CH₃), and the other ofR^(3a) and R^(3b) is H.

In some embodiments, n is 1 or 2. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, R^(a) is cyano, halogen, nitro, C₁-C₆ alkyl (e.g.,C₁-C₆ haloalkyl (e.g., CF₃) or C₁-C₆ hydroxyalkyl (e.g., CH₂OH)), C₁-C₆alkoxy (e.g., C₁-C₆ haloalkoxy), S(O)_(m)R^(b), NR^(c)R^(d), C(O)R^(e),or C(O)OR^(f). In some embodiments, R^(a) is cyano, halogen (e.g., F orCl), or nitro. In some embodiments, R^(a) is C₁-C₆ alkyl (e.g., CH₃,C₁-C₆ haloalkyl (e.g., CF₃) or C₁-C₆ hydroxyalkyl (e.g., CH₂OH)), orC₁-C₆ alkoxy (e.g., C₁-C₆ haloalkoxy).

In some embodiments, R^(a) is S(O)_(m)R^(b), NR^(c)R^(d), C(O)R^(e), orC(O)OR^(f). In some embodiments, R^(a) is S(O)_(m)R^(b), wherein m is 0or 1 and R^(b) is C₁-C₆ alkyl (e.g., CH₃). In some embodiments, R^(a) isS(O)_(m)R^(b), wherein m is 0 and R^(b) is C₁-C₆ alkyl (e.g., CH₃). Insome embodiments, R^(a) is S(O)_(m)R^(b), wherein m is 1 and R^(b) isC₁-C₆ alkyl (e.g., CH₃). In some embodiments, R^(aa) is NR^(c)R^(d),wherein R^(c) and R^(d) are each independently H or C(O)R^(e) (e.g.,C(O)CH₃). In some embodiments, R^(a) is C(O)R^(e), wherein R^(e) isNR^(g)R^(h) (e.g., NH₂). In some embodiments, R^(a) is C(O)OR^(f),wherein R^(f) is H or C₁-C₆ alkyl (e.g., CH₃).

In some embodiments, n is 1 or 2, and R^(a) is cyano, halogen, nitro, orC₁-C₆ alkoxy. In some embodiments, n is 2, and R^(a) is halogen (e.g.,F, Cl). In some embodiments, n is 1 and R¹ is C₁-C₆ alkyl. In someembodiments, n is 1 and R^(a) is substituted C₁-C₆ alkyl (e.g., —CH₂OH).

In some embodiments, n is 2, and two R^(a) groups, together with theatoms to which they are attached, form a 6-membered aryl or heteroarylring (e.g., a phenyl or pyridyl ring). In some embodiments, n is 2, andtwo R^(a) groups, together with the atoms to which they are attached,form a 6-membered unsubstituted aryl or unsubstituted heteroaryl ring(e.g., a phenyl or pyridyl ring). In some embodiments, n is 2, and twoR^(a) groups, together with the atoms to which they are attached, form a6-membered substituted aryl or substituted heteroaryl ring (e.g., aphenyl or pyridyl ring). In some embodiments, the 6-membered substitutedaryl or substituted heteroaryl ring (e.g., a phenyl or pyridyl ring) issubstituted with cyano, halogen, nitro, C₁-C₆ alkyl (e.g., C₁-C₆haloalkyl (e.g., CF₃) or C₁-C₆ hydroxyalkyl (e.g., CH₂OH)), C₁-C₆ alkoxy(e.g., C₁-C₆ haloalkoxy), S(O)_(m)R^(b), NR^(c)R^(d), C(O)R^(e), orC(O)OR^(f).

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-a) or (I-b):

In some embodiments, X is N. In some embodiments, X is N, and Y and Zare CH.

In some embodiments, Y and Z are CH.

In some embodiments, Y is N. In some embodiments, Y is N, and X and Zare CH.

In some embodiments, Z is N. In some embodiments, X and Z are N, and Yis CH. In some embodiments, X, Y, and Z are N.

In some embodiments, R¹ is C₁-C₆ alkyl. In some embodiments, R¹ is —CH₃,—CH₂CH₃, or —CH(CH₃)₂. In some embodiments, R¹ is —CH₃. In someembodiments, R¹ is —CH₂CH₃. In some embodiments, R¹ is —CH(CH₃)₂.

In some embodiments, R² is C₁-C₆ alkyl. In some embodiments, R² is —CH₃.

In some embodiments, R² is C₁-C₆ haloalkyl. In some embodiments, R² is—CF₃.

In some embodiments, each of R^(3a) and R^(3b) is independently H or D.In some embodiments, each of R^(3a) and R^(3b) is independently H. Insome embodiments, each of R^(3a) and R^(3b) is independently D. In someembodiments, one of R^(3a) and R^(3b) is H, D, or C₁-C₆ alkyl (e.g.,CH₃), and the other of R^(3a) and R^(3b) is H. In some embodiments, oneof R^(3a) and R^(3b) is D or C₁-C₆ alkyl (e.g., CH₃), and the other ofR^(3a) and R^(3b) is H.

In some embodiments, n is 1 or 2. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, R^(a) is cyano, halogen, nitro, C₁-C₆ alkyl (e.g.,C₁-C₆ haloalkyl (e.g., CF₃) or C₁-C₆ hydroxyalkyl (e.g., CH₂OH)), C₁-C₆alkoxy (e.g., C₁-C₆ haloalkoxy), S(O)_(m)R^(b), NR^(c)R^(d), C(O)R^(e),or C(O)OR^(f). In some embodiments, R^(a) is cyano, halogen (e.g., F orCl), or nitro. In some embodiments, R^(a) is C₁-C₆ alkyl (e.g., CH₃,C₁-C₆ haloalkyl (e.g., CF₃) or C₁-C₆ hydroxyalkyl (e.g., CH₂OH)), orC₁-C₆ alkoxy (e.g., C₁-C₆ haloalkoxy).

In some embodiments, R^(a) is S(O)_(m)R^(b), NR^(c)R^(d), C(O)R^(e), orC(O)OR^(f). In some embodiments, R^(a) is S(O)_(m)R^(b), wherein m is 0or 1 and R^(b) is C₁-C₆ alkyl (e.g., CH₃). In some embodiments, R^(a) isS(O)_(m)R^(b), wherein m is 0 and R^(b) is C₁-C₆ alkyl (e.g., CH₃). Insome embodiments, R^(a) is S(O)_(m)R^(b), wherein m is 1 and R^(b) isC₁-C₆ alkyl (e.g., CH₃). In some embodiments, R^(a) is NR^(c)R^(d),wherein R^(c) and R^(d) are each independently H or C(O)R^(e) (e.g.,C(O)CH₃). In some embodiments, R^(a) is C(O)R^(e), wherein R^(e) isNR^(g)R^(h) (e.g., NH₂). In some embodiments, R^(a) is C(O)OR^(f),wherein R^(f) is H or C₁-C₆ alkyl (e.g., CH₃).

In some embodiments, n is 1 or 2, and R^(a) is cyano, halogen, nitro, orC₁-C₆ alkoxy. In some embodiments, n is 2, and R^(a) is halogen (e.g.,F, Cl). In some embodiments, n is 1 and R¹ is C₁-C₆ alkyl. In someembodiments, n is 1 and R^(a) is substituted C₁-C₆ alkyl (e.g., —CH₂OH).

In some embodiments, n is 2, and two R^(a) groups, together with theatoms to which they are attached, form a 6-membered aryl or heteroarylring (e.g., a phenyl or pyridyl ring). In some embodiments, n is 2, andtwo R^(a) groups, together with the atoms to which they are attached,form a 6-membered unsubstituted aryl or unsubstituted heteroaryl ring(e.g., a phenyl or pyridyl ring). In some embodiments, n is 2, and twoR^(a) groups, together with the atoms to which they are attached, form a6-membered substituted aryl or substituted heteroaryl ring (e.g., aphenyl or pyridyl ring). In some embodiments, the 6-membered substitutedaryl or substituted heteroaryl ring (e.g., a phenyl or pyridyl ring) issubstituted with cyano, halogen, nitro, C₁-C₆ alkyl (e.g., C₁-C₆haloalkyl (e.g., CF₃) or C₁-C₆ hydroxyalkyl (e.g., CH₂OH)), C₁-C₆ alkoxy(e.g., C₁-C₆ haloalkoxy), S(O)_(m)R^(b), NR^(c)R^(d), C(O)R^(e), orC(O)OR^(f).

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-c):

or a pharmaceutically acceptable salt thereof, wherein: each X, Y, and Zis independently CH or N; R¹ is C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆alkynyl, carbocyclyl, or heterocyclyl; R² is C₁-C₆alkyl (e.g., C₁-C₆haloalkyl), or C₁-C₆ alkoxy; R^(aa) is cyano, halogen, C₁-C₆ alkyl,C₁-C₆ alkoxy (e.g., C₁-C₆ haloalkoxy), or S(O)_(m)R^(b); or two R^(aa)groups, together with the atoms to which they are attached, form a6-membered aryl or heteroaryl ring; R^(b) is C₁-C₆ alkyl; m is 0 or 1;and n is 0, 1, 2, 3, or 4.

In some embodiments, X is N. In some embodiments, X is N, and Y and Zare CH.

In some embodiments, Y and Z are CH.

In some embodiments, Y is N. In some embodiments, Y is N, and X and Zare CH.

In some embodiments, Z is N. In some embodiments, X and Z are N, and Yis CH. In some embodiments, X, Y, and Z are N.

In some embodiments, R¹ is C₁-C₆ alkyl. In some embodiments, R¹ is —CH₃,—CH₂CH₃, or —CH(CH₃)₂.

In some embodiments, R² is C₁-C₆ alkyl. In some embodiments, R² is —CH₃.

In some embodiments, R² is C₁-C₆ haloalkyl. In some embodiments, R² is—CF₃.

In some embodiments, n is 1 or 2. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, R^(a) is cyano, halogen, C₁-C₆ alkyl (e.g., C₁-C₆haloalkyl (e.g., CF₃) or C₁-C₆ hydroxyalkyl (e.g., CH₂OH)), C₁-C₆ alkoxy(e.g., C₁-C₆ haloalkoxy), or S(O)_(m)R^(b). In some embodiments, R^(a)is cyano or halogen (e.g., F or Cl). In some embodiments, R^(a) is C₁-C₆alkyl (e.g., CH₃, C₁-C₆ haloalkyl (e.g., CF₃) or C₁-C₆ hydroxyalkyl(e.g., CH₂OH)), or C₁-C₆ alkoxy (e.g., C₁-C₆ haloalkoxy).

In some embodiments, R^(a) is S(O)_(m)R^(b). In some embodiments, R^(a)is S(O)_(m)R^(b), wherein m is 0 or 1 and R^(b) is C₁-C₆ alkyl (e.g.,CH₃). In some embodiments, R^(a) is S(O)_(m)R^(b), wherein m is 0 andR^(b) is C₁-C₆ alkyl (e.g., CH₃). In some embodiments, R^(a) isS(O)_(m)R^(b), wherein m is 1 and R^(b) is C₁-C₆ alkyl (e.g., CH₃).

In some embodiments, n is 1 or 2, and R^(a) is cyano, halogen, or C₁-C₆alkoxy. In some embodiments, n is 2, and R^(a) is halogen (e.g., F, Cl).In some embodiments, n is 1 and R¹ is C₁-C₆ alkyl. In some embodiments,n is 1 and R^(a) is substituted C₁-C₆ alkyl (e.g., —CH₂OH).

In some embodiments, the compound of Formula (I) (e.g., a compound ofFormula (I-a), (I-b), or (I-c)) is not a compound selected from thegroup of depicted in Table 1.

TABLE 1

In another aspect, provided is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: each X, Y, and Zis independently CH or N; G is-C(R^(3a))(R^(3b))(OR¹); R¹ is C₁-C₆alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl; R² is C₁-C₆ alkyl (e.g., C₁-C₆ haloalkyl), or C₁-C₆ alkoxy;each of R^(3a) and R^(3b) is independently H, D, or C₁-C₆ alkyl; R^(aa)is cyano, halogen, nitro, C₁-C₆ alkyl (e.g., C₁-C₆ haloalkyl or C₁-C₆hydroxyalkyl), C₁-C₆ alkoxy (e.g., C₁-C₆ haloalkoxy), S(O)_(m)R^(b),NR^(c)R^(d), C(O)R^(e), or C(O)OR^(f); R^(b) is C₁-C₆ alkyl,NR^(c)R^(d), or OR^(f); each of R^(c) and R^(d) is independently H,C₁-C₆ alkyl, C(O)R^(e), or C(O)OR^(f); R^(e) is C₁-C₆ alkyl orNR^(g)R^(h); R^(f) is H or C₁-C₆ alkyl; each of R^(g) and R^(h) isindependently H or C₁-C₆ alkyl; m is 0, 1, or 2; and n is 0, 1, 2, 3, or4.

In some embodiments, X is N. In some embodiments, X is N, and Y and Zare CH.

In some embodiments, Y and Z are CH.

In some embodiments, Y is N. In some embodiments, Y is N, and X and Zare CH.

In some embodiments, Z is N. In some embodiments, X and Z are N, and Yis CH. In some embodiments, X, Y, and Z are N.

In some embodiments, R¹ is C₁-C₆ alkyl. In some embodiments, R¹ is —CH₃,—CH₂CH₃, or —CH(CH₃)₂. In some embodiments, R¹ is —CH₃. In someembodiments, R¹ is —CH₂CH₃. In some embodiments, R¹ is —CH(CH₃)₂.

In some embodiments, R² is C₁-C₆ alkyl. In some embodiments, R² is —CH₃.

In some embodiments, R² is C₁-C₆ haloalkyl. In some embodiments, R² is—CF₃.

In some embodiments, each of R^(3a) and R^(3b) is independently H or D.In some embodiments, each of R^(3a) and R^(3b) is independently H. Insome embodiments, each of R^(3a) and R^(3b) is independently D. In someembodiments, one of R^(3a) and R^(3b) is H, D, or C₁-C₆ alkyl (e.g.,CH₃), and the other of R^(3a) and R^(3b) is H. In some embodiments, oneof R^(3a) and R^(3b) is D or C₁-C₆ alkyl (e.g., CH₃), and the other ofR^(3a) and R^(3b) is H.

In some embodiments, n is 1 or 2. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, R^(a) is cyano, halogen, nitro, C₁-C₆ alkyl (e.g.,C₁-C₆ haloalkyl (e.g., CF₃) or C₁-C₆ hydroxyalkyl (e.g., CH₂OH)), C₁-C₆alkoxy (e.g., C₁-C₆ haloalkoxy), S(O)_(m)R^(b), NR^(c)R^(d), C(O)R^(e),or C(O)OR^(f). In some embodiments, R^(a) is cyano, halogen (e.g., F orCl), or nitro. In some embodiments, R^(a) is C₁-C₆ alkyl (e.g., CH₃,C₁-C₆ haloalkyl (e.g., CF₃) or C₁-C₆ hydroxyalkyl (e.g., CH₂OH)), orC₁-C₆ alkoxy (e.g., C₁-C₆ haloalkoxy).

In some embodiments, R^(a) is S(O)_(m)R^(b), NR^(c)R^(d), C(O)R^(e), orC(O)OR^(f). In some embodiments, R^(a) is S(O)_(m)R^(b), wherein m is 0or 1 and R^(b) is C₁-C₆ alkyl (e.g., CH₃). In some embodiments, R^(a) isS(O)_(m)R^(b), wherein m is 0 and R^(b) is C₁-C₆ alkyl (e.g., CH₃). Insome embodiments, R^(a) is S(O)_(m)R^(b), wherein m is 1 and R^(b) isC₁-C₆ alkyl (e.g., CH₃). In some embodiments, R^(a) is NR^(c)R^(d),wherein R^(c) and R^(d) are each independently H or C(O)R^(e) (e.g.,C(O)CH₃). In some embodiments, R^(a) is C(O)R^(e), wherein R^(e) isNR^(g)R^(h) (e.g., NH₂). In some embodiments, R^(a) is C(O)OR^(f),wherein R^(f) is H or C₁-C₆ alkyl (e.g., CH₃).

In some embodiments, n is 1 or 2, and R^(a) is cyano, halogen, nitro, orC₁-C₆ alkoxy. In some embodiments, n is 2, and R^(a) is halogen (e.g.,F, Cl). In some embodiments, n is 1 and R¹ is C₁-C₆ alkyl. In someembodiments, n is 1 and R^(a) is substituted C₁-C₆ alkyl (e.g., —CH₂OH).

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-a) or (II-b):

In some embodiments, X is N. In some embodiments, X is N, and Y and Zare CH.

In some embodiments, Y and Z are CH.

In some embodiments, Y is N. In some embodiments, Y is N, and X and Zare CH.

In some embodiments, Z is N. In some embodiments, X and Z are N, and Yis CH. In some embodiments, X, Y, and Z are N.

In some embodiments, R¹ is C₁-C₆ alkyl. In some embodiments, R¹ is —CH₃,—CH₂CH₃, or —CH(CH₃)₂. In some embodiments, R¹ is —CH₃. In someembodiments, R¹ is —CH₂CH₃. In some embodiments, R¹ is —CH(CH₃)₂.

In some embodiments, R² is C₁-C₆ alkyl. In some embodiments, R² is —CH₃.

In some embodiments, R² is C₁-C₆ haloalkyl. In some embodiments, R² is—CF₃.

In some embodiments, each of R^(3a) and R^(3b) is independently H or D.In some embodiments, each of R^(3a) and R^(3b) is independently H. Insome embodiments, each of R^(3a) and R^(3b) is independently D. In someembodiments, one of R^(3a) and R^(3b) is H, D, or C₁-C₆ alkyl (e.g.,CH₃), and the other of R^(3a) and R^(3b) is H. In some embodiments, oneof R^(3a) and R^(3b) is D or C₁-C₆ alkyl (e.g., CH₃), and the other ofR^(3a) and R^(3b) is H.

In some embodiments, n is 1 or 2. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, R^(a) is cyano, halogen, nitro, C₁-C₆ alkyl (e.g.,C₁-C₆ haloalkyl (e.g., CF₃) or C₁-C₆ hydroxyalkyl (e.g., CH₂OH)), C₁-C₆alkoxy (e.g., C₁-C₆ haloalkoxy), S(O)_(m)R^(b), NR^(c)R^(d), C(O)R^(e),or C(O)OR^(f). In some embodiments, R^(a) is cyano, halogen (e.g., F orCl), or nitro. In some embodiments, R^(a) is C₁-C₆ alkyl (e.g., CH₃,C₁-C₆ haloalkyl (e.g., CF₃) or C₁-C₆ hydroxyalkyl (e.g., CH₂OH)), orC₁-C₆ alkoxy (e.g., C₁-C₆ haloalkoxy).

In some embodiments, R^(a) is S(O)_(m)R^(b), NR^(c)R^(d), C(O)R^(e), orC(O)OR^(f). In some embodiments, R^(a) is S(O)_(m)R^(b), wherein m is 0or 1 and R^(b) is C₁-C₆ alkyl (e.g., CH₃). In some embodiments, R^(a) isS(O)_(m)R^(b), wherein m is 0 and R^(b) is C₁-C₆ alkyl (e.g., CH₃). Insome embodiments, R^(a) is S(O)_(m)R^(b), wherein m is 1 and R^(b) isC₁-C₆ alkyl (e.g., CH₃). In some embodiments, R^(a) is NR^(c)R^(d),wherein R^(e) and R^(d) are each independently H or C(O)R^(e) (e.g.,C(O)CH₃). In some embodiments, R^(a) is C(O)R^(e), wherein R^(e) isNR^(g)R^(h) (e.g., NH₂). In some embodiments, R^(a) is C(O)OR^(f),wherein R^(f) is H or C₁-C₆ alkyl (e.g., CH₃).

In some embodiments, n is 1 or 2, and R^(a) is cyano, halogen, nitro, orC₁-C₆ alkoxy. In some embodiments, n is 2, and R^(a) is halogen (e.g.,F, Cl). In some embodiments, n is 1 and R¹ is C₁-C₆ alkyl. In someembodiments, n is 1 and R^(a) is substituted C₁-C₆ alkyl (e.g., —CH₂OH).

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-c):

or a pharmaceutically acceptable salt thereof, wherein: each X, Y, and Zis independently CH or N; R¹ is C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆alkynyl, carbocyclyl, or heterocyclyl; R² is C₁-C₆alkyl (e.g., C₁-C₆haloalkyl), or C₁-C₆ alkoxy; R^(a) is cyano, halogen, C₁-C₆ alkyl (e.g.,substituted C₁-C₆ alkyl (e.g., —CH₂OH)), C₁-C₆ alkoxy (e.g., C₁-C₆haloalkoxy), or S(O)_(m)R^(b); R^(b) is C₁-C₆ alkyl; m is 0 or 1; and nis 0, 1, 2, 3, or 4.

In some embodiments, X is N. In some embodiments, X is N, and Y and Zare CH.

In some embodiments, Y and Z are CH.

In some embodiments, Y is N. In some embodiments, Y is N, and X and Zare CH.

In some embodiments, Z is N. In some embodiments, X and Z are N, and Yis CH. In some embodiments, X, Y, and Z are N.

In some embodiments, R¹ is C₁-C₆ alkyl. In some embodiments, R¹ is —CH₃,—CH₂CH₃, or —CH(CH₃)₂.

In some embodiments, R² is C₁-C₆ alkyl. In some embodiments, R² is —CH₃.

In some embodiments, R² is C₁-C₆ haloalkyl. In some embodiments, R² is—CF₃.

In some embodiments, n is 1 or 2. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, R^(a) is cyano, halogen, C₁-C₆ alkyl (e.g., C₁-C₆haloalkyl (e.g., CF₃) or C₁-C₆ hydroxyalkyl (e.g., CH₂OH)), C₁-C₆ alkoxy(e.g., C₁-C₆ haloalkoxy), or S(O)_(m)R^(b). In some embodiments, R^(a)is cyano or halogen (e.g., F or Cl). In some embodiments, R^(a) is C₁-C₆alkyl (e.g., CH₃, C₁-C₆ haloalkyl (e.g., CF₃) or C₁-C₆ hydroxyalkyl(e.g., CH₂OH)), or C₁-C₆ alkoxy (e.g., C₁-C₆ haloalkoxy).

In some embodiments, R^(a) is S(O)_(m)R^(b). In some embodiments, R^(a)is S(O)_(m)R^(b), wherein m is 0 or 1 and R^(b) is C₁-C₆ alkyl (e.g.,CH₃). In some embodiments, R^(a) is S(O)_(m)R^(b), wherein m is 0 andR^(b) is C₁-C₆ alkyl (e.g., CH₃). In some embodiments, R^(a) isS(O)_(m)R^(b), wherein m is 1 and R^(b) is C₁-C₆ alkyl (e.g., CH₃).

In some embodiments, n is 1 or 2, and R^(a) is cyano, halogen, or C₁-C₆alkoxy. In some embodiments, n is 2, and R^(a) is halogen (e.g., F, Cl).In some embodiments, n is 1 and R¹ is C₁-C₆ alkyl. In some embodiments,n is 1 and R^(a) is substituted C₁-C₆ alkyl (e.g., —CH₂OH).

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-d):

In some embodiments, X is N. In some embodiments, Y and Z are CH. Insome embodiments, X is N, and Y and Z are CH.

In some embodiments, R¹ is C₁-C₆ alkyl. In some embodiments, R¹ is —CH₃,—CH₂CH₃, or —CH(CH₃)₂.

In some embodiments, R² is C₁-C₆ alkyl. In some embodiments, R² is —CH₃.

In some embodiments, R² is C₁-C₆ haloalkyl. In some embodiments, R² is—CF₃.

In some embodiments, n is 1 or 2. In some embodiments, n is 1. In someembodiments, n is 2.

In some embodiments, R^(a) is cyano, halogen, C₁-C₆ alkyl (e.g., C₁-C₆haloalkyl (e.g., CF₃) or C₁-C₆ hydroxyalkyl (e.g., CH₂OH)), C₁-C₆ alkoxy(e.g., C₁-C₆ haloalkoxy), or S(O)_(m)R^(b). In some embodiments, R^(a)is cyano or halogen (e.g., F or Cl). In some embodiments, R^(a) is C₁-C₆alkyl (e.g., CH₃, C₁-C₆ haloalkyl (e.g., CF₃) or C₁-C₆ hydroxyalkyl(e.g., CH₂OH)), or C₁-C₆ alkoxy (e.g., C₁-C₆ haloalkoxy).

In some embodiments, R^(a) is S(O)_(m)R^(b). In some embodiments, R^(a)is S(O)_(m)R^(b), wherein m is 0 or 1 and R^(b) is C₁-C₆ alkyl (e.g.,CH₃). In some embodiments, R^(a) is S(O)_(m)R^(b), wherein m is 0 andR^(b) is C₁-C₆ alkyl (e.g., CH₃). In some embodiments, R^(a) isS(O)_(m)R^(b), wherein m is 1 and R^(b) is C₁-C₆ alkyl (e.g., CH₃).

In some embodiments, the compound of Formula (II) is a compound ofFormula (II-e):

In some embodiments, R^(a) is C₁-C₆ alkyl. In some embodiments, R^(a) issubstituted C₁-C₆ alkyl (e.g., —CH₂OH)). In some embodiments, R^(a) isC₁-C₆ alkoxy (e.g., —OCH₃, —OCH₂(CH₃)₂, C₁-C₆ haloalkoxy (e.g., —OCF₃)).In some embodiments, R^(a) is S(O)_(m)R^(b). In some embodiments, m is 0or 1, and C₁-C₆ alkyl (e.g., —CH₃). In some embodiments, R^(a) is SCH₃or S(O)CH₃.

In some embodiments, the compound of Formula (II) (e.g., a compound ofFormula (II-a), (II-b), (II-c), (II-d), or (II-e)) is not a compoundselected from a compound of Table 1.

In some embodiments, the compound of Formula (I) is a compound ofFormula (III-a):

In some embodiments, the compound of Formula (I) is a compound ofFormula (III-b):

wherein R^(b) is C₁-C₆ alkyl (e.g., —CH₃) and m is 0 or 1.

In some embodiments, the compound of Formula (I) or Formula (II) isselected from:

pharmaceutically acceptable salt thereof.

In one aspect, provided is a compound selected from:

or a pharmaceutically acceptable salt thereof.

Pharmaceutical Compositions

In one aspect, the invention provides a pharmaceutical compositioncomprising a compound described herein (also referred to as the “activeingredient”) and a pharmaceutically acceptable excipient. In certainembodiments, the pharmaceutical composition comprises an effectiveamount of the active ingredient. In certain embodiments, thepharmaceutical composition comprises a therapeutically effective amountof the active ingredient. In certain embodiments, the pharmaceuticalcomposition comprises a prophylactically effective amount of the activeingredient.

The pharmaceutical compositions provided herein can be administered by avariety of routes including, but not limited to, oral (enteral)administration, parenteral (by injection) administration, rectaladministration, transdermal administration, intradermal administration,intrathecal administration, subcutaneous (SC) administration,intravenous (IV) administration, intramuscular (IM) administration, andintranasal administration.

Generally, the compounds provided herein are administered in aneffective amount. The amount of the compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

When used to prevent the onset of a CNS-disorder, the compounds providedherein will be administered to a subject at risk for developing thecondition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Subjects at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

The pharmaceutical compositions provided herein can also be administeredchronically (“chronic administration”). Chronic administration refers toadministration of a compound or pharmaceutical composition thereof overan extended period of time, e.g., for example, over 3 months, 6 months,1 year, 2 years, 3 years, 5 years, etc, or may be continuedindefinitely, for example, for the rest of the subject's life. Incertain embodiments, the chronic administration is intended to provide aconstant level of the compound in the blood, e.g., within thetherapeutic window over the extended period of time.

The pharmaceutical compostions described herein may be further deliveredusing a variety of dosing methods. For example, in certain embodiments,the pharmaceutical composition may be given as a bolus, e.g., in orderto raise the concentration of the compound in the blood to an effectivelevel. The placement of the bolus dose depends on the systemic levels ofthe active ingredient desired throughout the body, e.g., anintramuscular or subcutaneous bolus dose allows a slow release of theactive ingredient, while a bolus delivered directly to the veins (e.g.,through an IV drip) allows a much faster delivery which quickly raisesthe concentration of the active ingredient in the blood to an effectivelevel. In other embodiments, the pharmaceutical composition may beadministered as a continuous infusion, e.g., by IV drip, to providemaintenance of a steady-state concentration of the active ingredient inthe subject's body. Furthermore, in still yet other embodiments, thepharmaceutical composition may be administered as first as a bolus dose,followed by continuous infusion.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the compound is usually aminor component (from about 0.1 to about 50% by weight or preferablyfrom about 1 to about 40% by weight) with the remainder being variousvehicles or excipients and processing aids helpful for forming thedesired dosing form.

With oral dosing, one to five and especially two to four and typicallythree oral doses per day are representative regimens. Using these dosingpatterns, each dose provides from about 0.01 to about 20 mg/kg of thecompound provided herein, with preferred doses each providing from about0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses, generally in anamount ranging from about 0.01 to about 20% by weight, preferably fromabout 0.1 to about 20% by weight, preferably from about 0.1 to about 10%by weight, and more preferably from about 0.5 to about 15% by weight.

Injection dose levels range from about 0.1 mg/kg/hour to at least 20mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kgor more may also be administered to achieve adequate steady statelevels. The maximum total dose is not expected to exceed about 5 g/dayfor a 40 to 80 kg human patient.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable excipients knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable excipient and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s). When formulated as aointment, the active ingredients will typically be combined with eithera paraffinic or a water-miscible ointment base. Alternatively, theactive ingredients may be formulated in a cream with, for example anoil-in-water cream base. Such transdermal formulations are well-known inthe art and generally include additional ingredients to enhance thedermal penetration of stability of the active ingredients orFormulation. All such known transdermal formulations and ingredients areincluded within the scope provided herein.

The compounds provided herein can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The compound as described herein, e.g., a compound of Formula (I),(I-a), (I-b), (I-c), (II), (II-a), (II-b), (II-c), (II-d), (II-e),(III-a), or (III-b), can also be administered in sustained release formsor from sustained release drug delivery systems. A description ofrepresentative sustained release materials can be found in Remington'sPharmaceutical Sciences.

The present invention also relates to the pharmaceutically acceptableacid addition salt of a compound as described herein, e.g., a compoundof Formula (I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (II-c),(II-d), (II-e), (III-a), or (III-b). The acid which may be used toprepare the pharmaceutically acceptable salt is that which forms anon-toxic acid addition salt, i.e., a salt containing pharmacologicallyacceptable anions such as the hydrochloride, hydroiodide, hydrobromide,nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate,tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate,and the like.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound as described herein, e.g., a compound of Formula(I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (II-c), (II-d), (II-e),(III-a), or (III-b) and a pharmaceutically acceptable excipient, e.g., acomposition suitable for injection, such as for intravenous (IV)administration.

Pharmaceutically acceptable excipients include any and all diluents orother liquid vehicles, dispersion or suspension aids, surface activeagents, isotonic agents, preservatives, lubricants and the like, assuited to the particular dosage form desired, e.g., injection. Generalconsiderations in the formulation and/or manufacture of pharmaceuticalcompositions agents can be found, for example, in Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980), and Remington: The Science andPractice of Pharmacy, 21^(st) Edition (Lippincott Williams & Wilkins,2005).

For example, injectable preparations, such as sterile injectable aqueoussuspensions, can be formulated according to the known art using suitabledispersing or wetting agents and suspending agents. Exemplary excipientsthat can be employed include, but are not limited to, water, sterilesaline or phosphate-buffered saline, or Ringer's solution.

In certain embodiments, the pharmaceutical composition further comprisesa cyclodextrin derivative. The most common cyclodextrins are α-, β- andγ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucose units,respectively, optionally comprising one or more substituents on thelinked sugar moieties, which include, but are not limited to,substituted or unsubstituted methylated, hydroxyalkylated, acylated, andsulfoalkylether substitution. In certain embodiments, the cyclodextrinis a sulfoalkyl ether β-cyclodextrin, e.g., for example, sulfobutylether β-cyclodextrin, also known as Captisol®. See, e.g., U.S. Pat. No.5,376,645. In certain embodiments, the composition compriseshexapropyl-β-cyclodextrin. In a more particular embodiment, thecomposition comprises hexapropyl-β-cyclodextrin (10-50% in water).

The injectable composition can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

Generally, the compounds provided herein are administered in aneffective amount. The amount of the compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,response of the individual patient, the severity of the patient'ssymptoms, and the like.

The compositions are presented in unit dosage forms to facilitateaccurate dosing. The term “unit dosage forms” refers to physicallydiscrete units suitable as unitary dosages for human subjects and othermammals, each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include pre-filled, pre-measured ampules or syringes of theliquid compositions. In such compositions, the compound is usually aminor component (from about 0.1% to about 50% by weight or preferablyfrom about 1% to about 40% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form.

The compounds provided herein can be administered as the sole activeagent, or they can be administered in combination with other activeagents. In one aspect, the present invention provides a combination of acompound of the present invention and another pharmacologically activeagent. Administration in combination can proceed by any techniqueapparent to those of skill in the art including, for example, separate,sequential, concurrent, and alternating administration.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.General considerations in the formulation and/or manufacture ofpharmaceutical compositions can be found, for example, in Remington: TheScience and Practice of Pharmacy 21^(st) ed., Lippincott Williams &Wilkins, 2005.

In one aspect, provided is a kit comprising a solid compositioncomprising a compound as described herein, e.g., a compound of Formula(I), (I-a), (I-b), (I-c), (II), (II-a), (II-b), (II-c), (II-d), (II-e),(III-a), or (III-b) and a sterile diluent.

Methods of Use and Treatment

As generally described herein, the present invention is directed toC21-substituted neuroactive steroids designed, for example, to act asGABA modulators. In certain embodiments, such compounds are envisionedto be useful as therapeutic agents for the inducement of anesthesiaand/or sedation in a subject. In some embodiments, such compounds areenvisioned to be useful as therapeutic agents for treating a CNS-relateddisorder (e.g., sleep disorder, a mood disorder (e.g., depression, forexample severe depression or postpartum depression; or anxietydisorders), a schizophrenia spectrum disorder, a convulsive disorder, adisorder of memory and/or cognition, a movement disorder (e.g., tremor,for example essential tremor), a personality disorder, autism spectrumdisorder, pain, traumatic brain injury, a vascular disease, a substanceabuse disorder and/or withdrawal syndrome, or tinnitus) in a subject inneed (e.g., a subject with Rett syndrome, Fragile X syndrome, orAngelman syndrome).

Thus, in one aspect, the present invention provides a method of inducingsedation and/or anesthesia in a subject, comprising administering to thesubject an effective amount of a compound of the present invention or acomposition thereof. In certain embodiments, the compound isadministered by intravenous administration.

Earlier studies (see, e.g., Gee et al., European Journal ofPharmacology, 136:419-423 (1987)) demonstrated that certain3α-hydroxylated steroids are orders of magnitude more potent asmodulators of the GABA receptor complex (GRC) than others had reported(see, e.g., Majewska et al., Science 232:1004-1007 (1986); Harrison etal., J Pharmacol. Exp. Ther. 241:346-353 (1987)). Majewska et al. andHarrison et al. taught that 3α-hydroxylated-5-reduced steroids are onlycapable of much lower levels of effectiveness. In vitro and in vivoexperimental data have now demonstrated that the high potency of thesesteroids allows them to be therapeutically useful in the modulation ofbrain excitability via the GRC (see, e.g., Gee et al., European Journalof Pharmacology, 136:419-423 (1987); Wieland et al., Psychopharmacology118(1):65-71 (1995)).

Various synthetic steroids have also been prepared as neuroactivesteroids. See, for example, U.S. Pat. No. 5,232,917, which disclosesneuroactive steroid compounds useful in treating stress, anxiety,insomnia, seizure disorders, and mood disorders, that are amenable toGRC-active agents, such as depression, in a therapeutically beneficialmanner. Furthermore, it has been previously demonstrated that thesesteroids interact at a unique site on the GRC which is distinct fromother known sites of interaction (e.g., barbiturates, benzodiazepines,and GABA) where therapeutically beneficial effects on stress, anxiety,sleep, mood disorders and seizure disorders have been previouslyelicited (see, e.g., Gee, K. W. and Yamamura, H. I., “Benzodiazepinesand Barbiturates: Drugs for the Treatment of Anxiety, Insomnia andSeizure Disorders,” in Central Nervous System Disorders, Horvell, ed.,Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, K. G. and Morselli,P. L., “Psychopharmacology of GABAergic Drugs,” in Psychopharmacology:The Third Generation of Progress, H. Y. Meltzer, ed., Raven Press, N.Y.(1987), pp. 183-195; and Gee et al., European Journal of Pharmacology,136:419-423 (1987). These compounds are desirable for their duration,potency, and oral activity (along with other forms of administration).

Compounds of the present invention, as described herein, are generallydesigned to modulate GABA function, and therefore to act as neuroactivesteroids for the treatment and prevention of CNS-related conditions in asubject. Modulation, as used herein, refers to the inhibition orpotentiation of GABA receptor function. Accordingly, the compounds andpharmaceutical compositions provided herein find use as therapeutics forpreventing and/or treating CNS conditions in mammals including humansand non-human mammals. Thus, and as stated earlier, the presentinvention includes within its scope, and extends to, the recited methodsof treatment, as well as to the compounds for such methods, and to theuse of such compounds for the preparation of medicaments useful for suchmethods.

Exemplary CNS conditions related to GABA-modulation include, but are notlimited to, sleep disorders [e.g., insomnia], mood disorders [e.g.,depression, dysthymic disorder (e.g., mild depression), bipolar disorder(e.g., I and/or II), anxiety disorders (e.g., generalized anxietydisorder (GAD), social anxiety disorder), stress, post-traumatic stressdisorder (PTSD), compulsive disorders (e.g., obsessive compulsivedisorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia,schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g.,status epilepticus (SE)), seizures], disorders of memory and/orcognition [e.g., attention disorders (e.g., attention deficithyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's typedementia, Lewis body type dementia, vascular type dementia], movementdisorders [e.g., Huntington's disease, Parkinson's disease, tremor(e.g., essential tremor)], personality disorders [e.g., anti-socialpersonality disorder, obsessive compulsive personality disorder], autismspectrum disorders (ASD) [e.g., autism, monogenetic causes of autismsuch as synaptophathy's, e.g., Rett syndrome, Fragile X syndrome,Angelman syndrome], pain [e.g., neuropathic pain, injury related painsyndromes, acute pain, chronic pain], traumatic brain injury (TBI),vascular diseases [e.g., stroke, ischemia, vascular malformations],substance abuse disorders and/or withdrawal syndromes [e.g., addition toopiates, cocaine, and/or alcohol], and tinnitus.

In yet another aspect, provided is a combination of a compound of thepresent invention and another pharmacologically active agent. Thecompounds provided herein can be administered as the sole active agentor they can be administered in combination with other agents.Administration in combination can proceed by any technique apparent tothose of skill in the art including, for example, separate, sequential,concurrent and alternating administration.

In another aspect, provided is a method of treating or preventing brainexcitability in a subject susceptible to or afflicted with a conditionassociated with brain excitability, comprising administering to thesubject an effective amount of a compound of the present invention tothe subject.

In yet another aspect, provided is a method of treating or preventingstress or anxiety in a subject, comprising administering to the subjectin need of such treatment an effective amount of a compound of thepresent invention, or a composition thereof.

In yet another aspect, provided is a method of alleviating or preventingmovement disorder (e.g., tremor, for example essential tremor) in asubject, comprising administering to the subject in need of suchtreatment an effective amount of a compound of the present invention. Incertain embodiments the movement disorder is tremor. In certainembodiments the tremor is essential tremor.

In yet another aspect, provided is a method of alleviating or preventingseizure activity in a subject, comprising administering to the subjectin need of such treatment an effective amount of a compound of thepresent invention.

In yet another aspect, provided is a method of alleviating or preventinginsomnia in a subject, comprising administering to the subject in needof such treatment an effective amount of a compound of the presentinvention, or a composition thereof.

In yet another aspect, provided is a method of inducing sleep andmaintaining substantially the level of REM sleep that is found in normalsleep, wherein substantial rebound insomnia is not induced, comprisingadministering an effective amount of a compound of the presentinvention.

In yet another aspect, provided is a method of alleviating or preventingPMS or PND in a subject, comprising administering to the subject in needof such treatment an effective amount of a compound of the presentinvention.

In yet another aspect, provided is a method of treating or preventingmood disorders in a subject, comprising administering to the subject inneed of such treatment an effective amount of a compound of the presentinvention. In certain embodiments the mood disorder is an anxietydisorder. In certain embodiments the mood disorder is depression. Incertain embodiments the depression is severe depression. In certainembodiment the depression is postpartum depression.

In yet another aspect, provided is a method of inducing anesthesia in asubject, comprising administering to the subject an effective amount ofa compound of the present invention.

In yet another aspect, provided is a method of cognition enhancement ortreating memory disorder by administering to the subject atherapeutically effective amount of a compound of the present invention.In certain embodiments, the disorder is Alzheimer's disease. In certainembodiments, the disorder is Rett syndrome.

In yet another aspect, provided is a method of treating attentiondisorders by administering to the subject a therapeutically effectiveamount of a compound of the present invention. In certain embodiments,the attention disorder is ADHD.

In certain embodiments, the compound is administered to the subjectchronically. In certain embodiments, the compound is administered to thesubject orally, subcutaneously, intramuscularly, or intravenously.

Anesthesia/Sedation

Anesthesia is a pharmacologically induced and reversible state ofamnesia, analgesia, loss of responsiveness, loss of skeletal musclereflexes, decreased stress response, or all of these simultaneously.These effects can be obtained from a single drug which alone providesthe correct combination of effects, or occasionally with a combinationof drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to achievevery specific combinations of results. Anesthesia allows patients toundergo surgery and other procedures without the distress and pain theywould otherwise experience.

Sedation is the reduction of irritability or agitation by administrationof a pharmacological agent, generally to facilitate a medical procedureor diagnostic procedure.

Sedation and analgesia include a continuum of states of consciousnessranging from minimal sedation (anxiolysis) to general anesthesia.

Minimal sedation is also known as anxiolysis. Minimal sedation is adrug-induced state during which the patient responds normally to verbalcommands. Cognitive function and coordination may be impaired.Ventilatory and cardiovascular functions are typically unaffected.

Moderate sedation/analgesia (conscious sedation) is a drug-induceddepression of consciousness during which the patient respondspurposefully to verbal command, either alone or accompanied by lighttactile stimulation. No interventions are usually necessary to maintaina patent airway. Spontaneous ventilation is typically adequate.Cardiovascular function is usually maintained.

Deep sedation/analgesia is a drug-induced depression of consciousnessduring which the patient cannot be easily aroused, but respondspurposefully (not a reflex withdrawal from a painful stimulus) followingrepeated or painful stimulation. Independent ventilatory function may beimpaired and the patient may require assistance to maintain a patentairway. Spontaneous ventilation may be inadequate. Cardiovascularfunction is usually maintained.

General anesthesia is a drug-induced loss of consciousness during whichthe patient is not arousable, even to painful stimuli. The ability tomaintain independent ventilatory function is often impaired andassistance is often required to maintain a patent airway. Positivepressure ventilation may be required due to depressed spontaneousventilation or drug-induced depression of neuromuscular function.Cardiovascular function may be impaired.

Sedation in the intensive care unit (ICU) allows the depression ofpatients' awareness of the environment and reduction of their responseto external stimulation. It can play a role in the care of thecritically ill patient, and encompasses a wide spectrum of symptomcontrol that will vary between patients, and among individualsthroughout the course of their illnesses. Heavy sedation in criticalcare has been used to facilitate endotracheal tube tolerance andventilator synchronization, often with neuromuscular blocking agents.

In some embodiments, sedation (e.g., long-term sedation, continuoussedation) is induced and maintained in the ICU for a prolonged period oftime (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 week, 3 weeks, 1month, 2 months). Long-term sedation agents may have long duration ofaction. Sedation agents in the ICU may have short elimination half-life.

Procedural sedation and analgesia, also referred to as conscioussedation, is a technique of administering sedatives or dissociativeagents with or without analgesics to induce a state that allows asubject to tolerate unpleasant procedures while maintainingcardiorespiratory function.

Neuroendocrine Disorders and Dysfunction

Provided herein are methods that can be used for treating neuroendocrinedisorders and dysfunction. As used herein, “neuroendocrine disorder” or“neuroendocrine dysfunction” refers to a variety of conditions caused byimbalances in the body's hormone production directly related to thebrain. Neuroendocrine disorders involve interactions between the nervoussystem and the endocrine system. Because the hypothalamus and thepituitary gland are two areas of the brain that regulate the productionof hormones, damage to the hypothalamus or pituitary gland, e.g., bytraumatic brain injury, may impact the production of hormones and otherneuroendocrine functions of the brain.

Symptoms of neuroendocrine disorder include, but are not limited to,behavioral, emotional, and sleep-related symptoms, symptoms related toreproductive function, and somatic symptoms; including but not limitedto fatigue, poor memory, anxiety, depression, weight gain or loss,emotional lability, lack of concentration, attention difficulties, lossof lipido, infertility, amenorrhea, loss of muscle mass, increased bellybody fat, low blood pressure, reduced heart rate, hair loss, anemia,constipation, cold intolerance, and dry skin.

Neurodegenerative Diseases and Disorders

Provided herein are methods that can be used for treatingneurodegenerative diseases and disorders. The term “neurodegenerativedisease” includes diseases and disorders that are associated with theprogressive loss of structure or function of neurons, or death ofneurons. Neurodegenerative diseases and disorders include, but are notlimited to, Alzheimer's disease (including the associated symptoms ofmild, moderate, or severe cognitive impairment); amyotrophic lateralsclerosis (ALS); anoxic and ischemic injuries; ataxia and convulsion(including for the treatment and prevention and prevention of seizuresthat are caused by schizoaffective disorder or by drugs used to treatschizophrenia); benign forgetfulness; brain edema; cerebellar ataxiaincluding McLeod neuroacanthocytosis syndrome (MLS); closed head injury;coma; contusive injuries (e.g., spinal cord injury and head injury);dementias including multi-infarct dementia and senile dementia;disturbances of consciousness; Down syndrome; drug-induced ormedication-induced Parkinsonism (such as neuroleptic-induced acuteakathisia, acute dystonia, Parkinsonism, or tardive dyskinesia,neuroleptic malignant syndrome, or medication-induced postural tremor);epilepsy; fragile X syndrome; Gilles de la Tourette's syndrome; headtrauma; hearing impairment and loss; Huntington's disease; Lennoxsyndrome; levodopa-induced dyskinesia; mental retardation; movementdisorders including akinesias and akinetic (rigid) syndromes (includingbasal ganglia calcification, corticobasal degeneration, multiple systematrophy, Parkinsonism-ALS dementia complex, Parkinson's disease,postencephalitic parkinsonism, and progressively supranuclear palsy);muscular spasms and disorders associated with muscular spasticity orweakness including chorea (such as benign hereditary chorea,drug-induced chorea, hemiballism, Huntington's disease,neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea),dyskinesia (including tics such as complex tics, simple tics, andsymptomatic tics), myoclonus (including generalized myoclonus and focalcyloclonus), tremor (such as rest tremor, postural tremor, essentialtremor and intention tremor) and dystonia (including axial dystonia,dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, andfocal dystonia such as blepharospasm, oromandibular dystonia, andspasmodic dysphonia and torticollis); neuronal damage including oculardamage, retinopathy or macular degeneration of the eye; neurotoxicinjury which follows cerebral stroke, thromboembolic stroke, hemorrhagicstroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia,hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson'sdisease; seizure; status epilecticus; stroke; tinnitus; tubularsclerosis, and viral infection induced neurodegeneration (e.g., causedby acquired immunodeficiency syndrome (AIDS) and encephalopathies).Neurodegenerative diseases also include, but are not limited to,neurotoxic injury which follows cerebral stroke, thromboembolic stroke,hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia,amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methodsof treating or preventing a neurodegenerative disease also includetreating or preventing loss of neuronal function characteristic ofneurodegenerative disorder.

Epilepsy

Epilepsy is a brain disorder characterized by repeated seizures overtime. Types of epilepsy can include, but are not limited to generalizedepilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy,epilepsy with grand-mal seizures on awakening, West syndrome,Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy,frontal lobe epilepsy, benign focal epilepsy of childhood.

Status Epilepticus (SE)

Status epilepticus (SE) can include, e.g., convulsive statusepilepticus, e.g., early status epilepticus, established statusepilepticus, refractory status epilepticus, super-refractory statusepilepticus; non-convulsive status epilepticus, e.g., generalized statusepilepticus, complex partial status epilepticus; generalized periodicepileptiform discharges; and periodic lateralized epileptiformdischarges. Convulsive status epilepticus is characterized by thepresence of convulsive status epileptic seizures, and can include earlystatus epilepticus, established status epilepticus, refractory statusepilepticus, super-refractory status epilepticus. Early statusepilepticus is treated with a first line therapy. Established statusepilepticus is characterized by status epileptic seizures which persistdespite treatment with a first line therapy, and a second line therapyis administered. Refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline and a second line therapy, and a general anesthetic is generallyadministered. Super refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline therapy, a second line therapy, and a general anesthetic for 24hours or more.

Non-convulsive status epilepticus can include, e.g., focalnon-convulsive status epilepticus, e.g., complex partial non-convulsivestatus epilepticus, simple partial non-convulsive status epilepticus,subtle non-convulsive status epilepticus; generalized non-convulsivestatus epilepticus, e.g., late onset absence non-convulsive statusepilepticus, atypical absence non-convulsive status epilepticus, ortypical absence non-convulsive status epilepticus.

Compositions described herein can also be administered as a prophylacticto a subject having a CNS disorder e.g., a traumatic brain injury,status epilepticus, e.g., convulsive status epilepticus, e.g., earlystatus epilepticus, established status epilepticus, refractory statusepilepticus, super-refractory status epilepticus; non-convulsive statusepilepticus, e.g., generalized status epilepticus, complex partialstatus epilepticus; generalized periodic epileptiform discharges; andperiodic lateralized epileptiform discharges; prior to the onset of aseizure.

Seizure

A seizure is the physical findings or changes in behavior that occurafter an episode of abnormal electrical activity in the brain. The term“seizure” is often used interchangeably with “convulsion.” Convulsionsare when a person's body shakes rapidly and uncontrollably. Duringconvulsions, the person's muscles contract and relax repeatedly.

Based on the type of behavior and brain activity, seizures are dividedinto two broad categories: generalized and partial (also called local orfocal). Classifying the type of seizure helps doctors diagnose whetheror not a patient has epilepsy.

Generalized seizures are produced by electrical impulses from throughoutthe entire brain, whereas partial seizures are produced (at leastinitially) by electrical impulses in a relatively small part of thebrain. The part of the brain generating the seizures is sometimes calledthe focus.

There are six types of generalized seizures. The most common anddramatic, and therefore the most well known, is the generalizedconvulsion, also called the grand-mal seizure. In this type of seizure,the patient loses consciousness and usually collapses. The loss ofconsciousness is followed by generalized body stiffening (called the“tonic” phase of the seizure) for 30 to 60 seconds, then by violentjerking (the “clonic” phase) for 30 to 60 seconds, after which thepatient goes into a deep sleep (the “postictal” or after-seizure phase).During grand-mal seizures, injuries and accidents may occur, such astongue biting and urinary incontinence.

Absence seizures cause a short loss of consciousness (just a fewseconds) with few or no symptoms. The patient, most often a child,typically interrupts an activity and stares blankly. These seizuresbegin and end abruptly and may occur several times a day. Patients areusually not aware that they are having a seizure, except that they maybe aware of “losing time.”

Myoclonic seizures consist of sporadic jerks, usually on both sides ofthe body. Patients sometimes describe the jerks as brief electricalshocks. When violent, these seizures may result in dropping orinvoluntarily throwing objects.

Clonic seizures are repetitive, rhythmic jerks that involve both sidesof the body at the same time.

Tonic seizures are characterized by stiffening of the muscles.

Atonic seizures consist of a sudden and general loss of muscle tone,particularly in the arms and legs, which often results in a fall.

Seizures described herein can include epileptic seizures; acuterepetitive seizures; cluster seizures; continuous seizures; unremittingseizures; prolonged seizures; recurrent seizures; status epilepticusseizures, e.g., refractory convulsive status epilepticus, non-convulsivestatus epilepticus seizures; refractory seizures; myoclonic seizures;tonic seizures; tonic-clonic seizures; simple partial seizures; complexpartial seizures; secondarily generalized seizures; atypical absenceseizures; absence seizures; atonic seizures; benign Rolandic seizures;febrile seizures; emotional seizures; focal seizures; gelastic seizures;generalized onset seizures; infantile spasms; Jacksonian seizures;massive bilateral myoclonus seizures; multifocal seizures; neonatalonset seizures; nocturnal seizures; occipital lobe seizures; posttraumatic seizures; subtle seizures; Sylvan seizures; visual reflexseizures; or withdrawal seizures.

Movement Disorders

Also described herein are methods for treating a movement disorder. Asused herein, “movement disorders” refers to a variety of diseases anddisorders that are associated with hyperkinetic movement disorders andrelated abnormalities in muscle control. Exemplary movement disordersinclude, but are not limited to, Parkinson's disease and parkinsonism(defined particularly by bradykinesia), dystonia, chorea andHuntington's disease, ataxia, tremor (e.g., essential tremor), myoclonusand startle, tics and Tourette syndrome, Restless legs syndrome, stiffperson syndrome, and gait disorders.

Tremor

The methods described herein can be used to treat tremor, for examplecerebellar tremor or intention tremor, dystonic tremor, essentialtremor, orthostatic tremor, parkinsonian tremor, physiological tremor,psychogenic tremor, or rubral tremor. Tremor includes hereditary,degenerative, and idiopathic disorders such as Wilson's disease,Parkinson's disease, and essential tremor, respectively; metabolicdiseases (e.g., thyoid-parathyroid-, liver disease and hypoglycemia);peripheral neuropathies (associated with Charcot-Marie-Tooth,Roussy-Levy, diabetes mellitus, complex regional pain syndrome); toxins(nicotine, mercury, lead, CO, Manganese, arsenic, toluene); drug-induced(narcoleptics, tricyclics, lithium, cocaine, alcohol, adrenaline,bronchodilators, theophylline, caffeine, steroids, valproate,amiodarone, thyroid hormones, vincristine); and psychogenic disorders.Clinical tremor can be classified into physiologic tremor, enhancedphysiologic tremor, essential tremor syndromes (including classicalessential tremor, primary orthostatic tremor, and task- andposition-specific tremor), dystonic tremor, parkinsonian tremor,cerebellar tremor, Holmes' tremor (i.e., rubral tremor), palatal tremor,neuropathic tremor, toxic or drug-induced tremor, and psychogenictremor.

Tremor is an involuntary, at times rhythmic, muscle contraction andrelaxation that can involve oscillations or twitching of one or morebody parts (e.g., hands, arms, eyes, face, head, vocal folds, trunk,legs).

Cerebellar tremor or intention tremor is a slow, broad tremor of theextremities that occurs after a purposeful movement. Cerebellar tremoris caused by lesions in or damage to the cerebellum resulting from,e.g., tumor, stroke, disease (e.g., multiple sclerosis, an inheriteddegenerative disorder).

Dystonic tremor occurs in individuals affected by dystonia, a movementdisorder in which sustained involuntary muscle contractions causetwisting and repetitive motions and/or painful and abnormal postures orpositions. Dystonic tremor may affect any muscle in the body. Dystonictremors occurs irregularly and often can be relieved by complete rest.

Essential tremor or benign essential tremor is the most common type oftremor. Essential tremor may be mild and nonprogressive in some, and maybe slowly progressive, starting on one side of the body but affect bothsides within 3 years. The hands are most often affected, but the head,voice, tongue, legs, and trunk may also be involved. Tremor frequencymay decrease as the person ages, but severity may increase. Heightenedemotion, stress, fever, physical exhaustion, or low blood sugar maytrigger tremors and/or increase their severity. Symptoms generallyevolve over time and can be both visible and persistent following onset.

Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz)rhythmic muscle contractions that occurs in the legs and trunkimmediately after standing. Cramps are felt in the thighs and legs andthe patient may shake uncontrollably when asked to stand in one spot.Orthostatic tremor may occurs in patients with essential tremor.

Parkinsonian tremor is caused by damage to structures within the brainthat control movement. Parkinsonian tremor is often a precursor toParkinson's disease and is typically seen as a “pill-rolling” action ofthe hands that may also affect the chin, lips, legs, and trunk. Onset ofparkinsonian tremor typically begins after age 60. Movement starts inone limb or on one side of the body and can progress to include theother side.

Physiological tremor can occur in normal individuals and have noclinical significance. It can be seen in all voluntary muscle groups.Physiological tremor can be caused by certain drugs, alcohol withdrawl,or medical conditions including an overactive thyroid and hypoglycemia.The tremor classically has a frequency of about 10 Hz.

Psychogenic tremor or hysterical tremor can occur at rest or duringpostural or kinetic movement. Patient with psychogenic tremor may have aconversion disorder or another psychiatric disease.

Rubral tremor is characterized by coarse slow tremor which can bepresent at rest, at posture, and with intention. The tremor isassociated with conditions that affect the red nucleus in the midbrain,classical unusual strokes.

Parkinson's Disease affects nerve cells in the brain that producedopamine. Symptoms include muscle rigidity, tremors, and changes inspeech and gait. Parkinsonism is characterized by tremor, bradykinesia,rigidity, and postural instability. Parkinsonism shares symptons foundin Parkinson's Disease, but is a symptom complex rather than aprogressive neurodegenerative disease.

Dystonia is a movement disorder characterized by sustained orintermittent muscle contractions causing abnormal, often repetitivemovements or postures. Dystonic movements can be patterned, twisting,and may be tremulous. Dystonia is often initiated or worsened byvoluntary action and associated with overflow muscle activation.

Chorea is a neurological disorder characterized by jerky involuntarymovements typically affecting the shoulders, hips, and face.Huntington's Disease is an inherited disease that causes nerve cells inthe brain to waste away. Symptoms include uncontrolled movements,clumsiness, and balance problems. Huntington's disease can hinder walk,talk, and swallowing.

Ataxia refers to the loss of full control of bodily movements, and mayaffect the fingers, hands, arms, legs, body, speech, and eye movements.

Myloclonus and Startle is a response to a sudden and unexpectedstimulus, which can be acoustic, tactile, visual, or vestibular.

Tics are an involuntary movement usually onset suddenly, brief,repetitive, but non-rhythmical, typically imitating normal behavior andoften occurring out of a background of normal activity. Tics can beclassified as motor or vocal, motor tics associated with movements whilevocal tics associated with sound. Tics can be characterized as simple orcomplex. For example simple motor tics involve only a few musclesrestricted to a specific body part. Tourette Syndrome is an inheritedneuropsychiatric disorder with onset in childhood, characterized bymultiple motor tics and at least one vocal tic.

Restless Legs Syndrome is a neurologic sensorimotor disordercharacterized by an overwhelming urge to move the legs when at rest.

Stiff Person Syndrome is a progressive movement disorder characterizedby involuntary painful spasms and rigidity of muscles, usually involvingthe lower back and legs. Stiff-legged gait with exaggerated lumbarhyperlordosis typically results. Characteristic abnormality on EMGrecordings with continuous motor unit activity of the paraspinal axialmuscles is typically observed. Variants include “stiff-limb syndrome”producing focal stiffness typically affecting distal legs and feet.

Gait disorders refer to an abnormalitiy in the manner or style ofwalking, which results from neuromuscular, arthritic, or other bodychanges. Gait is classified according to the system responsible forabnormal locomotion, and include hemiplegic gait, diplegic gait,neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait,ataxic gait, and sensory gait.

Mood Disorders

Clinical depression is also known as major depression, major depressivedisorder (MDD), unipolar depression, unipolar disorder, and recurrentdepression, and refers to a mental disorder characterized by pervasiveand persistent low mood that is accompanied by low self-esteem and lossof interest or pleasure in normally enjoyable activities. Some peoplewith clinical depression have trouble sleeping, lose weight, andgenerally feel agitated and irritable. Clinical depression affects howan individual feels, thinks, and behaves and may lead to a variety ofemotional and physical problems. Individuals with clinical depressionmay have trouble doing day-to-day activities and make an individual feelas if life is not worth living.

Postnatal depression (PND) is also referred to as postpartum depression(PPD), and refers to a type of clinical depression that affects womenafter childbirth. Symptoms can include sadness, fatigue, changes insleeping and eating habits, reduced sexual desire, crying episodes,anxiety, and irritability.

Atypical depression (AD) is characterized by mood reactivity (e.g.,paradoxical anhedonia) and positivity, significant weight gain orincreased appetite. Patients suffering from AD also may have excessivesleep or somnolence (hypersomnia), a sensation of limb heaviness, andsignificant social impairment as a consequence of hypersensitivity toperceived interpersonal rejection.

Melancholic depression is characterized by loss of pleasure (anhedonia)in most or all activities, failures to react to pleasurable stimuli,depressed mood more pronounced than that of grief or loss, excessiveweight loss, or excessive guilt.

Psychotic major depression (PMD) or psychotic depression refers to amajor depressive episode, in particular of melancholic nature, where theindividual experiences psychotic symptoms such as delusions andhallucinations.

Catatonic depression refers to major depression involving disturbancesof motor behavior and other symptoms. An individual may become mute andstuporose, and either is immobile or exhibits purposeless or bizarremovements.

Seasonal affective disorder (SAD) refers to a type of seasonaldepression wherein an individual has seasonal patterns of depressiveepisodes coming on in the fall or winter.

Dysthymia refers to a condition related to unipolar depression, wherethe same physical and cognitive problems are evident. They are not assevere and tend to last longer (e.g., at least 2 years).

Double depression refers to fairly depressed mood (dysthymia) that lastsfor at least 2 years and is punctuated by periods of major depression.

Depressive Personality Disorder (DPD) refers to a personality disorderwith depressive features.

Recurrent Brief Depression (RBD) refers to a condition in whichindividuals have depressive episodes about once per month, each episodelasting 2 weeks or less and typically less than 2-3 days.

Minor depressive disorder or minor depression refers to a depression inwhich at least 2 symptoms are present for 2 weeks.

Bipolar disorder or manic depressive disorder causes extreme mood swingsthat include emotional highs (mania or hypomania) and lows (depression).During periods of mania the individual may feel or act abnormally happy,energetic, or irritable. They often make poorly thought out decisionswith little regard to the consequences. The need for sleep is usuallyreduced. During periods of depression there may be crying, poor eyecontact with others, and a negative outlook on life. The risk of suicideamong those with the disorder is high at greater than 6% over 20 years,while self harm occurs in 30-40%. Other mental health issues such asanxiety disorder and substance use disorder are commonly associated withbipolar disorder.

Depression caused by chronic medical conditions refers to depressioncaused by chronic medical conditions such as cancer or chronic pain,chemotherapy, chronic stress.

Treatment-resistant depression refers to a condition where theindividuals have been treated for depression, but the symptoms do notimprove. For example, antidepressants or psychological counseling(psychotherapy) do not ease depression symptoms for individuals withtreatment-resistant depression. In some cases, individuals withtreatment-resistant depression improve symptoms, but come back.Refractory depression occurs in patients suffering from depression whoare resistant to standard pharmacological treatments, includingtricyclic antidepressants, MAOIs, SSRIs, and double and triple uptakeinhibitors and/or anxiolytic drugs, as well as non-pharmacologicaltreatments (e.g., psychotherapy, electroconvulsive therapy, vagus nervestimulation and/or transcranial magnetic stimulation).

Suicidality, suicidal ideation, suicidal behavior refers to the tendencyof an individual to commit suicide. Suicidal ideation concerns thoughtsabout or an unusual preoccupation with suicide. The range of suicidalideation varies greatly, from e.g., fleeting thoughts to extensivethoughts, detailed planning, role playing, incomplete attempts. Symptomsinclude talking about suicide, getting the means to commit suicide,withdrawing from social contact, being preoccupied with death, feelingtrapped or hopeless about a situation, increasing use of alcohol ordrugs, doing risky or self-destructive things, saying goodbye to peopleas if they won't be seen again.

Symptoms of depression include persistent anxious or sad feelings,feelings of helplessness, hopelessness, pessimism, worthlessness, lowenergy, restlessness, difficulty sleeping, sleeplessness, irritability,fatigue, motor challenges, loss of interest in pleasurable activities orhobbies, loss of concentration, loss of energy, poor self-esteem,absence of positive thoughts or plans, excessive sleeping, overeating,appetite loss, insomnia, self-harm, thoughts of suicide, and suicideattempts. The presence, severity, frequency, and duration of symptomsmay vary on a case to case basis. Symptoms of depression, and relief ofthe same, may be ascertained by a physician or psychologist (e.g., by amental state examination).

Anxiety Disorders

Provided herein are methods for treating anxiety disorders. Anxietydisorder is a blanket term covering several different forms of abnormaland pathological fear and anxiety. Current psychiatric diagnosticcriteria recognize a wide variety of anxiety disorders.

Generalized anxiety disorder is a common chronic disorder characterizedby long-lasting anxiety that is not focused on any one object orsituation. Those suffering from generalized anxiety experiencenon-specific persistent fear and worry and become overly concerned witheveryday matters. Generalized anxiety disorder is the most commonanxiety disorder to affect older adults.

In panic disorder, a person suffers from brief attacks of intense terrorand apprehension, often marked by trembling, shaking, confusion,dizziness, nausea, difficulty breathing. These panic attacks, defined bythe APA as fear or discomfort that abruptly arises and peaks in lessthan ten minutes, can last for several hours and can be triggered bystress, fear, or even exercise; although the specific cause is notalways apparent. In addition to recurrent unexpected panic attacks, adiagnosis of panic disorder also requires that said attacks have chronicconsequences: either worry over the attacks' potential implications,persistent fear of future attacks, or significant changes in behaviorrelated to the attacks. Accordingly, those suffering from panic disorderexperience symptoms even outside of specific panic episodes. Often,normal changes in heartbeat are noticed by a panic sufferer, leadingthem to think something is wrong with their heart or they are about tohave another panic attack. In some cases, a heightened awareness(hypervigilance) of body functioning occurs during panic attacks,wherein any perceived physiological change is interpreted as a possiblelife threatening illness (i.e. extreme hypochondriasis).

Obsessive compulsive disorder is a type of anxiety disorder primarilycharacterized by repetitive obsessions (distressing, persistent, andintrusive thoughts or images) and compulsions (urges to perform specificacts or rituals). The OCD thought pattern may be likened tosuperstitions insofar as it involves a belief in a causativerelationship where, in reality, one does not exist. Often the process isentirely illogical; for example, the compulsion of walking in a certainpattern may be employed to alleviate the obsession of impending harm.And in many cases, the compulsion is entirely inexplicable, simply anurge to complete a ritual triggered by nervousness. In a minority ofcases, sufferers of OCD may only experience obsessions, with no overtcompulsions; a much smaller number of sufferers experience onlycompulsions.

The single largest category of anxiety disorders is that of phobia,which includes all cases in which fear and anxiety is triggered by aspecific stimulus or situation. Sufferers typically anticipateterrifying consequences from encountering the object of their fear,which can be anything from an animal to a location to a bodily fluid.

Post-traumatic stress disorder or PTSD is an anxiety disorder whichresults from a traumatic experience. Post-traumatic stress can resultfrom an extreme situation, such as combat, rape, hostage situations, oreven serious accident. It can also result from long term (chronic)exposure to a severe stressor, for example soldiers who endureindividual battles but cannot cope with continuous combat. Commonsymptoms include flashbacks, avoidant behaviors, and depression.

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodimentdescribed herein that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions and methodsprovided herein and are not to be construed in any way as limiting theirscope.

Materials and Methods

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures.For example, starting materials described herein can be prepared fromthe methods and procedures described in PCT/US2014/052417. It will beappreciated that where typical or preferred process conditions (i.e.,reaction temperatures, times, mole ratios of reactants, solvents,pressures, etc.) are given, other process conditions can also be usedunless otherwise stated. Optimum reaction conditions may vary with theparticular reactants or solvent used, but such conditions can bedetermined by one skilled in the art by routine optimization.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

The compounds provided herein may be isolated and purified by knownstandard procedures. Such procedures include (but are not limited to)recrystallization, column chromatography, HPLC, or supercritical fluidchromatography (SFC). The following schemes are presented with detailsas to the preparation of representative heteroaryls and heterocyclylsthat have been listed herein. The compounds provided herein may beprepared from known or commercially available starting materials andreagents by one skilled in the art of organic synthesis. Exemplarychiral columns available for use in the separation/purification of theenantiomers/diastereomers provided herein include, but are not limitedto, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD,CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ andCHIRALCEL® OK.

¹H-NMR reported herein (e.g., for intermediates) may be a partialrepresentation of the full NMR spectrum of a compound, e.g., a compounddescribed herein. For example, the reported ¹H NMR may exclude orpartially represent the region between δ (ppm) of about 1 to about 2.5ppm. For example, the reported ¹H NMR may include residual solvent orwater.

Exemplary general method for preparative HPLC: Column: Waters RBridgeprep 10 μm C18, 19*250 mm. Mobile phase: aectonitrile, water (NH₄HCO₃)(30 L water, 24 g NH₄HCO₃, 30 mL NH₃.H₂O). Flow rate: 25 mL/min

Exemplary general method for analytical HPLC: Mobile phase: A: water (10mM NH₄HCO₃), B: acetonitrile Gradient: 5%-95% B in 1.6 or 2 min Flowrate: 1.8 or 2 mL/min; Column: XBridge C18, 4.6*50 mm, 3.5 μm at 45 C.

Abbreviation List

THF: tetrahydrofuran; PE: petroleum ether; DCM: dichloromethane; EtOAc:ethylacetate; PCC: pyridinium chlorochromate; t-BuOK: potassiumtert-butoxide; TBAF: tetra-n-butylammonium fluoride; TBSC1:tert-Butyl(chloro)dimethylsilane; DMP: Dess-Martin periodinane;(i-PrO)₄Ti: titanium tetraisopropoxide; LAH: lithium aluminium hydride;MAD: methyl aluminum bis(2,6-di-t-butyl-4-methylphenoxide); BHT:2,6-di-t-butyl-p-cresol (butylated hydroxytoluene); DIEA:diisopropylethylamine; NCS: N-chlorosuccinimide.

Synthetic Methods Example 1. Synthesis of Compounds 1 and 2

To a solution of C1 (1 g, 2.26 mmol) in acetone (150 mL) was added K₂CO₃(937 mg) and 5-chloro-2H-benzo[d][1,2,3]triazole (520 mg, 3.39 mmol).The mixture was stirred at 25° C. for 2 hrs. The solvent was removed byrotary evaporator. To the mixture was added water (80 mL) and EtOAc (120mL). The organic layer was separated. The aqueous phase was extractedwith EtOAc (2×100 mL). The combined organic layers were washed withbrine (200 mL), dried over Na₂SO₄, filtered and evaporated to affordcrude product, which was purified by preparative HPLC to give twocompounds. The further purification was conducted by SFC to affordcompound 2 (157 mg, 13%) and compound 1 (100 mg, 9%).

1: ¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, J=9.3 Hz, 1H), 7.37-7.31 (m, 2H),5.44-5.30 (m, 2H), 3.54 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.22 (d, J=9.3Hz, 1H), 2.74-2.66 (m, 1H), 2.28-1.71 (m, 8H), 1.70-1.46 (m, 9H),1.45-1.20 (m, 9H), 0.71 (s, 3H). LCMS R_(t)=0.943 min in 1.5 minchromatography, MS ESI calcd. for C₂₉H₄₁ClN₃O₃[M+H]⁺ 514, found 514.

2: ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J=1.5 Hz, 1H), 7.44 (dd, J=8.7 Hz,1.6 Hz, 1H), 7.24-7.29 (m, 1H), 5.46-5.31 (m, 2H), 3.53 (d, J=9.0 Hz,1H), 3.33 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.74-2.63 (m, 1H), 2.38-1.67(m, 9H), 1.57-1.06 (m, 17H), 0.69 (s, 3H). LCMS R_(t)=0.945 min in 1.5min chromatography, MS ESI calcd. for C₂₉H₄₁ClN₃O₃[M+H]⁺ 514, found 514.

Example 2. Synthesis of Compounds 7 and 8

The synthesis of compounds 7 and 8 were carried out in a similar mannerto the protocol outlined in Example 1.

7: ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.34 (m, 1H), 7.08-7.04 (m, 1H),5.41-5.34 (m, 2H), 3.55 (d, J=9.2 Hz, 1H), 3.48-3.41 (m, 2H), 3.26 (d,J=9.2 Hz, 1H), 2.73-2.68 (m, 1H), 2.25-2.10 (m, 2H), 2.00-1.90 (m, 2H),1.85-1.35 (m, 17H), 1.30-1.10 (m, 8H), 0.69 (s, 3H). LCMS R_(t)=2.503min in 3 min chromatography, MS ESI calcd. forC₃₀H₄₀F₂N₃O₂[M+H—H₂O]⁺512, found 512.

8: ¹H NMR (400 MHz, CDCl₃) δ 7.66-7.63 (m, 1H), 7.32-7.25 (m, 1H),5.58-5.50 (m, 2H), 3.56 (d, J=9.2 Hz, 1H), 3.48-3.41 (m, 2H), 3.26 (d,J=9.2 Hz, 1H), 2.70-2.61 (m, 1H), 2.25-2.10 (m, 2H), 2.00-1.90 (m, 2H),1.85-1.35 (m, 17H), 1.30-1.10 (m, 8H), 0.72 (s, 3H). LCMS R_(t)=2.168min in 3 min chromatography, MS ESI calcd. forC₃₀H₄₀F₂N₃O₂[M+H—H₂O]⁺512, found 512.

Example 3. Synthesis of Compounds 9 and 10

To a solution of C1 (1 g, 2.26 mmol) in acetone (150 mL) was added K₂CO₃(937 mg, 6.78 mmol) and 4,6-difluoro-2H-benzo[d][1,2,3]triazole (525 mg,3.39 mmol). The mixture was stirred at 25° C. for 2 hrs. The solvent wasremoved by rotary evaporator. To the mixture was added water (80 mL) andEtOAc (120 mL). The organic layer was separated. The aqueous phase wasextracted with EtOAc (2×100 mL). The combined organic layers were washedwith brine (200 mL), dried over Na₂SO₄, filtered and concentrated toafford crude product, which was purified by preparative HPLC to give amixture of two compounds. The further purification was conducted by SFCto give 9 (168.9 mg, crude) and 10 (25 mg, 2%). Compound 9 was purifiedby SFC second time to afford compound 9 (91.3 mg, 8%).

9: ¹H NMR (400 MHz, CDCl₃) δ 6.86 (dt, J=1.8, 9.5 Hz, 1H), 6.79 (dd,J=1.6, 7.4 Hz, 1H), 5.44-5.30 (m, 2H), 3.52 (d, J=9.0 Hz, 1H), 3.32 (s,3H), 3.21 (d, J=9.0 Hz, 1H), 2.74-2.64 (m, 1H), 2.26-1.64 (m, 9H),1.59-1.05 (m, 17H), 0.68 (s, 3H). LCMS Rt=0.929 min in 1.5 minchromatography, MS ESI calcd. for C₂₉H₃₈F₂N₃O₂[M+H—H₂O]⁺498, found 498.

10: ¹H NMR (400 MHz, CDCl₃) δ 7.31 (dd, J=1.8, 8.3 Hz, 1H), 6.95-6.87(m, 1H), 5.57-5.44 (m, 2H), 3.55 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.21(d, J=9.0 Hz, 1H), 2.69-2.60 (m, 1H), 2.28-1.65 (m, 7H), 1.56-1.08 (m,19H), 0.73 (s, 3H). LCMS Rt=1.389 min in 2 min chromatography, MS ESIcalcd. for C₂₉H₃₈F₂N₃O₂[M+H-H₂O]⁺498, found 498.

Example 4. Synthesis of Compounds 11, 12, and 13

To a solution of C1 (200 mg, 0.453 mmol) in acetone (4 mL) was addedK₂CO₃ (186 mg) and 6-chloro-2H-[1,2,3]triazolo[4,5-b]pyridine (104 mg,0.679 mmol). The mixture was stirred at 25° C. for 4 hrs. The solventwas removed by rotary evaporator. To the mixture was added water (4 mL)and EtOAc (5 mL). The organic layer was separated. The aqueous phase wasextracted with EtOAc (2×5 mL). The combined organic layers was washedwith brine (7 mL), dried over Na₂SO₄. The solvent was removed by therotary evaporator, and the residue was purified by preparative HPLC togive compound 11 (89.6 mg, 38%), compound 12 (28.2 mg, 12%) and compound13 (33.6 mg, 14%).

11: (400 MHz, CDCl₃) δ 8.68 (d, J=2.0 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H),5.53-5.45 (m, 1H), 5.40-5.32 (m, 1H), 3.54 (d, J=9.0 Hz, 1H), 3.33 (s,3H), 3.22 (d, J=9.0 Hz, 1H), 2.78-2.69 (m, 1H), 2.29-2.12 (m, 2H),2.02-1.61 (m, 9H), 1.55-1.11 (m, 15H), 0.70 (s, 3H). LCMS Rt=0.906 minin 1.5 min chromatography, MS ESI calcd. for C₂₈H₃₈ClN₄O₂[M+H-H₂O]⁺497,found 497.

12: (400 MHz, CDCl₃) δ 8.58 (d, J=2.0 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H),5.56-5.42 (m, 2H), 3.55 (d, J=9.0 Hz, 1H), 3.34 (s, 3H), 3.23 (d, J=9.0Hz, 1H), 2.78-2.69 (m, 1H), 2.29-2.17 (m, 2H), 2.02-1.62 (m, 8H),1.55-1.10 (m, 16H), 0.72 (s, 3H). LCMS Rt=0.932 min in 1.5 minchromatography, MS ESI calcd. for C₂₈H₃₈ClN₄O₂[M+H-H₂O]⁺497, found 497.

13: (400 MHz, CDCl₃) δ 8.73 (d, J=2.3 Hz, 1H), 8.22 (d, J=2.3 Hz, 1H),5.59-5.47 (m, 2H), 3.54 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.21 (d, J=9.0Hz, 1H), 2.70-2.59 (m, 1H), 2.28-1.62 (m, 9H), 1.56-1.08 (m, 17H), 0.73(s, 3H). LCMS Rt=0.928 min in 1.5 min chromatography, 5-95AB, purity100%, MS ESI calcd. for C₂₈H₃₈ClN₄O₂[M+H-H₂O]⁺497, found 497.

Example 5. Synthesis of Compounds 14 and 15

To a solution of C1 (150 mg, 0.339 mmol) in acetone (3 mL) was addedK₂CO₃ (139 mg) and 6-fluoro-2H-indazole (69.1 mg, 0.508 mmol). Themixture was stirred at 25° C. for 4 hrs. The solvent was removed byrotary evaporator. To the mixture was added water (4 mL) and EtOAc (5mL). The organic layer was separated. The aqueous phase was extractedwith EtOAc (2×5 mL). The combined organic layers was washed with brine(7 mL), dried over Na₂SO₄. The solvent was removed by the rotaryevaporator, and the residue was purified by preparative HPLC to givecompound 14 (11.5 mg, 7%) and 15 (60.2 mg, 36%).

14: ¹H NMR (400 MHz, CDCl₃) δ 7.93 (s, 1H), 7.63 (dd, J=5.3, 9.0 Hz,1H), 7.31-7.22 (m, 1H), 6.95-6.83 (m, 1H), 5.25-5.07 (m, 2H), 3.53 (d,J=9.0 Hz, 1H), 3.32 (s, 3H), 3.20 (d, J=9.0 Hz, 1H), 2.62 (t, J=8.5 Hz,1H), 2.28-2.15 (m, 1H), 2.15-2.06 (m, 1H), 2.01-1.67 (m, 8H), 1.56-1.07(m, 16H), 0.69 (s, 3H). LCMS Rt=0.915 min in 1.5 min chromatography, MSESI calcd. for C₃₀H₄₂FN₂O₃[M+H]⁺ 497, found 497.

15: ¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H), 7.68 (dd, J=5.0, 8.8 Hz,1H), 6.93 (dt, J=2.0, 9.0 Hz, 1H), 6.84 (d, J=9.0 Hz, 1H), 5.14-5.00 (m,2H), 3.54 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.21 (d, J=9.0 Hz, 1H),2.67-2.56 (m, 1H), 2.25-2.06 (m, 2H), 1.98-1.86 (m, 2H), 1.82-1.62 (m,5H), 1.58-1.06 (m, 17H), 0.70 (s, 3H). LCMS Rt=0.935 min in 1.5 minchromatography, MS ESI calcd. for C₃₀H₄₂FN₂O₃[M+H]⁺ 497, found 497.

Example 6. Synthesis of Compounds 16 and 17

To a solution of C1 (150 mg, 0.339 mmol) in acetone (3 mL) was addedK₂CO₃ (139 mg) and 5-fluoro-2H-indazole (69.1 mg, 0.508 mmol). Themixture was stirred at 25° C. for 4 hrs. The solvent was removed byrotary evaporator. To the mixture was added water (4 mL) and EtOAc (5mL). The organic layer was separated. The aqueous phase was extractedwith EtOAc (2×5 mL). The combined organic layers was washed with brine(7 mL), dried over Na₂SO₄, filtered and evaporated to afford crudeproduct, which was purified by preparative HPLC to give compound 16(20.4 mg, 12%) and compound 17 (69.3 mg, 41%).

16: ¹H NMR (400 MHz, CDCl₃) δ 7.89 (s, 1H), 7.67 (dd, J=4.5, 9.3 Hz,1H), 7.28-7.21 (m, 1H), 7.14-7.06 (m, 1H), 5.27-5.12 (m, 2H), 3.54 (d,J=9.0 Hz, 1H), 3.33 (s, 3H), 3.20 (d, J=9.0 Hz, 1H), 2.67-2.58 (m, 1H),2.27-2.06 (m, 2H), 2.02-1.62 (m, 10H), 1.51-1.11 (m, 14H), 0.69 (s, 3H).LCMS Rt=0.913 min in 1.5 min chromatography, MS ESI calcd. forC₃₀H₄₂FN₂O₃[M+H]⁺ 497, found 497.

17: ¹H NMR (400 MHz, CDCl₃) δ 8.00 (s, 1H), 7.40-7.33 (m, 1H), 7.18-7.11(m, 2H), 5.18-5.06 (m, 2H), 3.54 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.21(d, J=9.0 Hz, 1H), 2.61 (t, J=8.9 Hz, 1H), 2.24-2.06 (m, 2H), 2.02-1.85(m, 3H), 1.82-1.62 (m, 4H), 1.56-1.06 (m, 17H), 0.69 (s, 3H). LCMSRt=0.939 min in 1.5 min chromatography, MS ESI calcd. for C₃₀H₄₂FN₂O₃[M+H]⁺ 497, found 497.

Example 7. Synthesis of Compounds 18 and 19

To a solution of C1 (150 mg, 0.339 mmol) in acetone (3 mL) was addedK₂CO₃ (139 mg) and 2H-benzo[d][1,2,3]triazole (60.5 mg, 0.508 mmol). Themixture was stirred at 25° C. for 4 hrs. The solvent was removed byrotary evaporator. To the mixture was added water (4 mL) and EtOAc (5mL). The organic layer was separated. The aqueous phase was extractedwith EtOAc (2×5 mL). The combined organic layers was washed with brine(7 mL), dried over Na₂SO₄, filtered and evaporated to give crudeproduct, which was purified by preparative HPLC to afford compound 18(51.9 mg, 32%) and compound 19 (8.9 mg, 6%).

18: ¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J=8.3 Hz, 1H), 7.52-7.44 (m, 1H),7.41-7.29 (m, 2H), 5.46-5.35 (m, 2H), 3.53 (d, J=9.0 Hz, 1H), 3.32 (s,3H), 3.21 (d, J=9.0 Hz, 1H), 2.73-2.64 (m, 1H), 2.14 (d, J=12.0 Hz, 2H),2.00-1.86 (m, 2H), 1.81-1.62 (m, 6H), 1.55-1.10 (m, 16H), 0.70 (s, 3H).LCMS Rt=0.894 min in 1.5 min chromatography, MS ESI calcd. forC₂₉H₄₂N₃O₃ [M+H]⁺ 480, found 480.

19: ¹H NMR (400 MHz, CDCl₃) δ 7.93-7.83 (m, 2H), 7.45-7.35 (m, 2H),5.57-5.46 (m, 2H), 3.55 (d, J=9.0 Hz, 1H), 3.34 (s, 3H), 3.21 (d, J=9.0Hz, 1H), 2.69-2.60 (m, 1H), 2.29-2.11 (m, 2H), 1.99-1.87 (m, 2H),1.84-1.63 (m, 5H), 1.57-1.10 (m, 17H), 0.74 (s, 3H). LCMS Rt=0.931 minin 1.5 min chromatography, MS ESI calcd. for C₂₉H₄₀N₃O₂ [M+H—H₂O]⁺462,found 462.

Example 8. Synthesis of Compound 20

To a solution of C1 (200 mg, 0.453 mmol) in acetone (4 mL) was addedK₂CO₃ (186 mg) and 5-fluoro-2H-benzo[d][1,2,3]triazole (137 mg, 0.679mmol). The mixture was stirred at 25° C. for 4 hrs. The solvent wasremoved by rotary evaporator. To the mixture was added water (5 mL) andEtOAc (6 mL). The organic layer was separated. The aqueous phase wasextracted with EtOAc (2×6 mL). The combined organic layers was washedwith brine (7 mL), dried over Na₂SO₄, filtered and evaporated to givecrude product, which was purified by preparative HPLC to afford compound20 (34.3 mg, 13%).

20: ¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, J=9.3 Hz, 1H), 7.72 (s, 1H),7.30-7.25 (m, 1H), 5.58-5.44 (m, 2H), 3.55 (d, J=9.0 Hz, 1H), 3.33 (s,3H), 3.21 (d, J=9.0 Hz, 1H), 2.70-2.61 (m, 1H), 2.31-2.09 (m, 2H),1.95-1.63 (m, 6H), 1.59-1.06 (m, 18H), 0.73 (s, 3H). LCMS Rt=1.035 minin 1.5 min chromatography, MS ESI calcd. for C₃₀H₃₉F₃N₃O₃[M+H—H₂O]⁺546,found 546.

Example 9. Synthesis of Compounds 21 and 22

Step 1. To a solution of C1 (300 mg, 0.679 mmol) in acetone (6 mL) wasadded K₂CO3 (280 mg) and 4-(methylthio)-1H-pyrazole (115 mg, 1.01 mmol).The mixture was stirred at 25° C. for 4 hrs. The solvent was removed byrotary evaporator. To the mixture was added water (6 mL) and EtOAc (8mL). The organic layer was separated. The aqueous phase was extractedwith EtOAc (2×8 mL). The combined organic layers was washed with brine(10 mL), dried over Na₂SO₄, filtered and evaporated to give a residue,which was purified by preparative HPLC to afford compound 21 (30.3 mg,75%).

21: (400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.41 (s, 1H), 4.94-4.87 (m, 1H),4.86-4.78 (m, 1H), 3.53 (d, J=9.0 Hz, 1H), 3.32 (s, 3H), 3.18 (d, J=9.0Hz, 1H), 2.61-2.52 (m, 1H), 2.34 (s, 3H), 2.24-2.13 (m, 1H), 2.08-1.99(m, 1H), 1.96-1.86 (m, 2H), 1.79-1.61 (m, 8H), 1.52-1.35 (m, 5H), 1.27(s, 9H), 0.66 (s, 3H). LCMS Rt=0.900 min in 1.5 min chromatography, MSESI calcd. for C₂₇H₄₂N₂O₃SN_(a) [M+Na]⁺497, found 497.

Step 2. To a solution of compound 21 (105 mg, 0.221 mmol) in DCM (20 mL)was added MCPBA (42 mg, 0.243 mmol) at −78° C. The reaction mixture wasstirred at −78° C. for 6 hrs. The reaction was quenched with saturatedaqueous Na₂S₂O₃ (15 mL) and extracted with EtOAc (2×40 mL). The combinedorganic phase was washed with saturated aqueous NaHCO₃ (20 mL) and brine(2×40 mL), dried over Na₂SO₄, and concentrated in vacuum. The residuewas purified by column chromatograph on silica gel (PE/EtOAc=5/1 toEtOH/MeOH=9/1) to give compound 22 (60 mg, 56%).

22: ¹H NMR (400 MHz, CDCl₃) δ 7.84-7.77 (m, 2H), 5.06-4.83 (m, 2H),3.56-3.48 (m, 1H), 3.31 (s, 3H), 3.18 (d, J=9.0 Hz, 1H), 2.88 (d, J=1.5Hz, 3H), 2.63-2.54 (m, 1H), 2.26-2.12 (m, 1H), 2.08-1.65 (m, 9H),1.54-1.38 (m, 6H), 1.34-1.03 (m, 10H), 0.65 (s, 3H). LCMS Rt=1.075 minin 2 min chromatography, MS ESI calcd. for C₂₇H₄₁N₂O₃S [M+H—H₂O]⁺473,found 473.

Example 10. Synthesis of Compounds 23 and 24

To a solution of C1 (150 mg, 0.339 mmol) in acetone (3 mL) was addedK₂CO₃ (139 mg) and 5-chloro-4-fluoro-2H-benzo[d] (87.1 mg, 0.508 mmol).The mixture was stirred at 25° C. for 4 hrs. The solvent was removed byrotary evaporator. To the mixture was added water (3 mL) and EtOAc (4mL). The organic layer was separated. The aqueous phase was extractedwith EtOAc (2×4 mL). The combined organic layers was washed with brine(6 mL), dried over Na₂SO₄, filtered and evaporated to give the crudeproduct, which was purified by preparative HPLC to give compound 23(69.2 mg, 38%) and compound 24 (40.3 mg, 22%).

23: ¹H NMR (400 MHz, CDCl₃) δ 7.47 (dd, J=6.1, 8.7 Hz, 1H), 7.07 (d,J=8.8 Hz, 1H), 5.48-5.33 (m, 2H), 3.53 (d, J=9.0 Hz, 1H), 3.33 (s, 3H),3.22 (d, J=9.3 Hz, 1H), 2.74-2.66 (m, 1H), 2.27-2.09 (m, 2H), 2.02-1.88(m, 2H), 1.85-1.58 (m, 7H), 1.52-1.09 (m, 15H), 0.70 (s, 3H). LCMSRt=1.378 min in 2 min chromatography, MS ESI calcd. forC₂₉H₃₈ClFN₃O₂[M+H—H₂O]⁺514, found 514.

24: ¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J=9.0 Hz, 1H), 7.36 (dd, J=6.5,9.0 Hz, 1H), 5.57-5.46 (m, 2H), 3.55 (d, J=9.0 Hz, 1H), 3.34 (s, 3H),3.21 (d, J=9.0 Hz, 1H), 2.70-2.60 (m, 1H), 2.29-2.09 (m, 2H), 1.96-1.60(m, 7H), 1.56-1.13 (m, 17H), 0.73 (s, 3H). LCMS Rt=1.431 min in 2 minchromatography, MS ESI calcd. for C₂₉H₃₈ClFN₃O₂[M+H—H₂O]⁺514, found 514.

Example 11. Synthesis of Compounds 25, 26, and 27

To a solution of C1 (200 mg, 0.453 mmol) in acetone (4 mL) was addedK₂CO₃ (186 mg) and 5-methoxy-2H-benzo [d][1,2,3]triazole (101 mg, 0.679mmol). The mixture was stirred at 25° C. for 4 hrs. The solvent wasremoved by rotary evaporator. To the mixture was added water (5 mL) andEtOAc (6 mL). The organic layer was separated. The aqueous phase wasextracted with EtOAc (2×6 mL). The combined organic layers was washedwith brine (7 mL), dried over Na₂SO₄, filtered and evaporated to givecrude product, which was purified by preparative HPLC to afford compound25 (50.8 mg, 22%) and compound 26 (20.5 mg, 9%), compound 27 (28 mg,12%).

25: ¹H NMR (400 MHz, CDCl₃) δ 7.92 (d, 2=9.0 Hz, 1H), 7.26 (s, 1H),7.04-6.99 (m, 1H), 6.60 (d, J=2.0 Hz, 1H), 5.42-5.24 (m, 2H), 3.86 (s,3H), 3.54 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 3.21 (d, J=9.0 Hz, 1H),2.73-2.63 (m, 1H), 2.29-2.11 (m, 2H), 1.97-1.64 (m, 6H), 1.57-1.05 (m,17H), 0.71 (s, 3H). LCMS Rt=0.886 min in 1.5 min chromatography, MS ESIcalcd. for C₃₀H₄₄N₃O₄ [M+H]⁺ 510, found 510.

26: ¹H NMR (400 MHz, CDCl₃) δ 7.37 (d, J=1.8 Hz, 1H), 7.22-7.17 (m, 1H),7.16-7.10 (m, 1H), 5.41-5.29 (m, 2H), 3.88 (s, 3H), 3.53 (d, J=9.0 Hz,1H), 3.32 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.71-2.61 (m, 1H), 2.28-2.07(m, 2H), 1.97-1.61 (m, 8H), 1.55-1.08 (m, 16H), 0.69 (s, 3H). LCMSRt=0.885 min in 1.5 min chromatography, MS ESI calcd. for C₃₀H₄₄N₃O₄[M+H]⁺ 510, found 510.

27: ¹H NMR (400 MHz, CDCl₃) δ 7.76-7.70 (m, 1H), 7.10-7.04 (m, 2H),5.49-5.37 (m, 2H), 3.88 (s, 3H), 3.55 (d, J=9.0 Hz, 1H), 3.33 (s, 3H),3.20 (d, J=9.0 Hz, 1H), 2.66-2.57 (m, 1H), 2.28-2.08 (m, 2H), 2.02-1.59(m, 8H), 1.54-1.11 (m, 16H), 0.72 (s, 3H). LCMS Rt=1.319 min in 2 minchromatography, MS ESI calcd. for C₃₀H₄₄N₃O₄ [M+H]⁺ 510, found 510.

Example 12. Synthesis of Compounds 28, 29, and 30

To a solution of C1 (150 mg, 0.339 mmol) in acetone (3 mL) was addedK₂CO₃ (140 mg) and 4-methoxy-2H-benzo[d][1,2,3]triazole (75.7 mg, 0.508mmol). The mixture was stirred at 25° C. for 4 hrs. The solvent wasremoved by rotary evaporator. To the mixture was added water (3 mL) andEtOAc (4 mL). The organic layer was separated. The aqueous phase wasextracted with EtOAc (2×5 mL). The combined organic layers was washedwith brine (8 mL), dried over Na₂SO₄, filtered and evaporated to affordcrude product, which was purified by preparative HPLC to give compound29 (10.4 mg, 6%), compound 28 (15.6 mg, 9%) and compound 30 (11.1 mg,6%).

28: ¹H NMR (400 MHz, CDCl₃) δ 7.40 (t, J=8.0 Hz, 1H), 6.88 (d, J=8.3 Hz,1H), 6.72 (d, J=7.8 Hz, 1H), 5.38 (s, 2H), 4.14 (s, 3H), 3.56 (d, J=9.0Hz, 1H), 3.35 (s, 3H), 3.23 (d, J=9.0 Hz, 1H), 2.74-2.63 (m, 1H),2.28-2.12 (m, 2H), 1.99-1.89 (m, 2H), 1.83-1.69 (m, 4H), 1.58-1.43 (m,7H), 1.34-1.29 (m, 6H), 0.97-0.81 (m, 5H), 0.70 (s, 3H). LCMS Rt=0.892min in 1.5 min chromatography, MS ESI calcd. for C₃₀H₄₄N₃O₄ [M+H]⁺ 510,found 510.

29: ¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J=8.3 Hz, 1H), 7.25-7.21 (m, 1H),6.76 (d, J=7.5 Hz, 1H), 5.57 (s, 2H), 3.89 (s, 3H), 3.56 (d, J=9.0 Hz,1H), 3.34 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.71-2.61 (m, 1H), 2.26-2.08(m, 2H), 1.93 (d, J=6.3 Hz, 2H), 1.84-1.63 (m, 5H), 1.53-1.10 (m, 17H),0.75-0.68 (m, 3H). LCMS Rt=0.898 min in 1.5 min chromatography, MS ESIcalcd. for C₃₀H₄₄N₃O₄ [M+H]⁺ 510, found 510.

30: ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J=8.5 Hz, 1H), 7.34-7.27 (m, 1H),6.64 (d, J=7.5 Hz, 1H), 5.49 (s, 2H), 4.07-4.00 (m, 3H), 3.55 (d, J=9.0Hz, 1H), 3.33 (s, 3H), 3.19 (d, J=9.0 Hz, 1H), 2.65-2.58 (m, 1H),2.26-2.08 (m, 2H), 1.97-1.62 (m, 8H), 1.54-1.36 (m, 8H), 0.95-0.79 (m,8H), 0.72 (s, 3H). LCMS Rt=2.092 min in 3 min chromatography, MS ESIcalcd. for C₃₀H₄₄N₃O₄ [M+H]⁺ 510, found 510.

Example 13. Synthesis of Compounds 31, 32, and 33

To a solution of C1 (150 mg, 0.339 mmol) in acetone (3 mL) was addedK₂CO₃ (139 mg) and 5-chloro-4-fluoro-2H-benzo[d] (87.1 mg, 0.508 mmol).The mixture was stirred at 25° C. for 4 hrs. The solvent was removed byrotary evaporator. To the mixture was added water (3 mL) and EtOAc (4mL). The organic layer was separated. The aqueous phase was extractedwith EtOAc (2×4 mL). The combined organic layers was washed with brine(6 mL), dried over Na₂SO₄, filtered and evaporated to afford crudeproduct, which was purified by preparative HPLC to give compound 31 (5.2mg, 3%), compound 32 (40.3 mg, 22%) and compound 33 (33, 69.2 mg, 38%).

31: ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=8.8 Hz, 1H), 7.35 (dd, J=6.4,8.7 Hz, 1H), 5.58-5.46 (m, 2H), 3.55 (d, J=9.0 Hz, 1H), 3.34 (s, 3H),3.22 (d, J=9.0 Hz, 1H), 2.71 (t, J=8.9 Hz, 1H), 2.27-2.09 (m, 2H),2.03-1.62 (m, 7H), 1.44-1.12 (m, 16H), 0.88 (t, J=6.7 Hz, 1H), 0.72 (s,3H). LCMS Rt=1.328 min in 2 min chromatography, MS ESI calcd. forC₂₉H₃₈ClFN₃O₂[M+H—H₂O]⁺514, found 514.

32: ¹H NMR (400 MHz, CDCl₃) δ 7.63 (d, J=9.0 Hz, 1H), 7.36 (dd, J=6.5,9.0 Hz, 1H), 5.57-5.46 (m, 2H), 3.55 (d, J=9.0 Hz, 1H), 3.34 (s, 3H),3.21 (d, J=9.0 Hz, 1H), 2.70-2.60 (m, 1H), 2.29-2.09 (m, 2H), 1.96-1.60(m, 7H), 1.56-1.13 (m, 17H), 0.73 (s, 3H). LCMS Rt=1.431 min in 2 minchromatography, MS ESI calcd. for C₂₉H₃₈ClFN₃O₂[M+H—H₂O]⁺514, found 514.

33: ¹H NMR (400 MHz, CDCl₃) δ 7.47 (dd, J=6.1, 8.7 Hz, 1H), 7.07 (d,J=8.8 Hz, 1H), 5.48-5.33 (m, 2H), 3.53 (d, J=9.0 Hz, 1H), 3.33 (s, 3H),3.22 (d, J=9.3 Hz, 1H), 2.74-2.66 (m, 1H), 2.27-2.09 (m, 2H), 2.02-1.88(m, 2H), 1.85-1.58 (m, 7H), 1.52-1.09 (m, 15H), 0.70 (s, 3H). LCMSRt=1.378 min in 2 min chromatography, MS ESI calcd. forC₂₉H₃₈ClFN₃O₂[M+H—H₂O]⁺514, found 514.

Example 14. Synthesis of Compounds 34 and 35

Step 1. To a solution of A1 (300 mg, 0.679 mmol) in acetone (6 mL) wasadded K₂CO₃ (280 mg, 2.03 mmol) and 4-(methylthio)-1H-pyrazole (115 mg,1.01 mmol). The mixture was stirred at 25° C. for 4 hrs. The solvent wasremoved by rotary evaporator. To the mixture was added water (6 mL) andEtOAc (8 mL). The organic layer was separated. The aqueous phase wasextracted with EtOAc (2×8 mL). The combined organic layers was washedwith brine (10 mL), dried over Na₂SO₄, filtered and evaporated to afforda crude product, which was purified by preparative HPLC to give compound34 (120 mg, 36%).

34: ¹H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 7.41 (s, 1H), 4.95-4.77 (m,2H), 3.49-3.43 (m, 1H), 3.40-3.34 (m, 1H), 3.28 (s, 3H), 2.58 (t, J=8.7Hz, 1H), 2.34 (s, 3H), 2.26-2.14 (m, 1H), 2.07-1.98 (m, 2H), 1.77-1.63(m, 4H), 1.57-1.44 (m, 5H), 1.41-0.79 (m, 14H), 0.69 (s, 3H). LCMSRt=0.927 min in 1.5 min chromatography, MS ESI calcd. forC₂₇H₄₂N₂O₃SN_(a) [M+Na]⁺497, found 497.

Step 2. To a solution of compound 34 (50 mg, 0.105 mmol) in DCM (20 mL)was added MCPBA (19.8 mg, 0.115 mmol) at −78° C. The reaction mixturewas stirred at −78° C. for 6 hrs. The reaction was quenched withsaturated Na₂S₂O₃ (15 mL). The reaction mixture was extracted with EtOAc(2×40 mL). The combined organic phase was washed with saturated NaHCO₃(20 mL), brine, dried over Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by column chromatograph on silica gel(PE/EtOAc=5/1) to give compound 35 (27.5 mg, 53%).

35: ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=3.0 Hz, 2H), 5.06-4.84 (m, 2H),3.49-3.43 (m, 1H), 3.40-3.34 (m, 1H), 3.28 (s, 3H), 2.89 (d, J=0.8 Hz,3H), 2.60 (t, J=8.8 Hz, 1H), 2.28-2.15 (m, 1H), 2.08-1.97 (m, 2H),1.81-1.60 (m, 7H), 1.50-0.80 (m, 16H), 0.69 (s, 3H). LCMS Rt=0.812 minin 1.5 min chromatography, MS ESI calcd. for C₂₇H₄₁N₂O₃S [M+H—H₂O]⁺473,found 473.

Example 15. Synthesis of Compound 36

To a solution of A1 (150 mg, 0.339 mmol) in acetone (3 mL) was added1H-imidazole-2-carbonitrile (47.2 mg, 0.508 mmol), followed by K₂CO₃(93.7 mg, 0.678 mmol). The resulting reaction mixture was stirred at 40°C. for 16 hrs. To the mixture was added water (10 mL) and extracted withEtOAc (3×8 mL). The combined organic phase was dried over Na₂SO₄,filtered and concentrated to give a residue, which was purified bycombi-flash (PE: EtOAc=100%-80%) to compound 36 (57 mg, 37%) as a whitesolid.

36: ¹H NMR (400 MHz, CDCl₃) δ 7.24 (s, 1H), 7.03 (s, 1H), 4.96-4.83 (m,2H), 3.48-3.35 (m, 2H), 3.28 (s, 3H), 2.62 (t, J=8.8 Hz, 1H), 2.22-2.01(m, 4H), 1.85-1.63 (m, 4H), 1.62-1.10 (m, 16H), 1.05-0.86 (m, 2H), 0.72(s, 3H). LCMS Rt=1.256 min in 2 min chromatography, MS ESI calcd. forC₂₇H₄₀N₃O₃ [M+H]⁺ 454, found 454.

Example 16. Synthesis of Compound 37

To a solution of A1 (150 mg, 0.339 mmol) in acetone (3 mL) was added4-methoxy-1H-pyrazole (49.8 mg, 0.508 mmol), followed by K₂CO₃ (93.7 mg,0.678 mmol). The resulting reaction mixture was stirred at 40° C. for 16hrs. To the mixture was added water (10 mL) and extracted with EtOAc(3×8 mL). The combined organic phase was concentrated to give a residue,which was purified by preparative HPLC to give compound 37 (10 mg, 7%),

37: ¹H NMR (400 MHz, CDCl₃) δ 7.28 (s, 1H), 7.09 (s, 1H), 4.87-4.75 (m,2H), 3.76 (s, 3H), 3.47-3.31 (m, 2H), 3.28 (s, 3H), 2.56 (t, J=8.8 Hz,1H), 2.17-2.01 (m, 4H), 1.71-1.42 (m, 8H), 1.41-0.92 (m, 12H), 0.91-0.84(m, 2H), 0.69 (s, 3H). LCMS Rt=1.256 min in 2 min chromatography, MS ESIcalcd. for C₂₇H₄₃N₂O₄ [M+H]⁺ 459, found 459.

Example 17. Synthesis of Compound 38

To a solution of A1 (150 mg, 0.339 mmol) in acetone (3 mL) was added4-isopropoxy-1H-pyrazole (64 mg, 0.508 mmol), followed by K₂CO₃ (93.7mg, 0.678 mmol). The resulting reaction mixture was stirred at 40° C.for 16 hrs. To the mixture was added water (10 mL) and extracted withEtOAc (3×8 mL). The combined organic phases was concentrated to give aresidue, which was purified by preparative HPLC to yield compound 38 (36mg, 22%) as an off-white solid.

38: ¹H NMR (400 MHz, CDCl₃) δ 7.26 (s, 1H), 7.06 (s, 1H), 4.84-4.77 (m,2H), 4.18-4.14 (m, 1H), 3.47-3.35 (m, 2H), 3.28 (s, 3H), 2.55 (t, J=8.8Hz, 1H), 2.04-1.70 (m, 3H), 1.68-1.45 (m, 10H), 1.41-1.01 (m, 17H),0.98-0.83 (m, 2H), 0.69 (s, 3H). LCMS Rt=1.338 min in 2 minchromatography, MS ESI calcd. for C₂₉H₄₆N₂O₄Na [M+Na]⁺509, found 509.

Example 18. Synthesis of Compound 39

To a solution of A1 (150 mg, 0.339 mmol) in acetone (2 mL) was added(1H-pyrazol-4-yl)methanol (49.8 mg, 0.508 mmol), followed by K₂CO₃ (93.7mg, 0.678 mmol). The resulting reaction mixture was stirred at 40° C.for 2 hrs. To the mixture was added water (10 mL) and extracted withEtOAc (3×8 mL). The combined organic phases was concentrated to give aresidue, which was purified by preparative HPLC to give compound 39 (6mg, 4%) as an off-white solid.

39: (yield 4%): ¹H NMR (400 MHz, CDCl₃) δ 7.54 (s, 1H), 7.41 (s, 1H),4.96-4.61 (m, 2H), 4.61 (s, 2H), 3.47-3.36 (m, 2H), 3.28 (s, 3H), 2.59(t, J=9.2 Hz, 1H), 2.05-2.01 (m, 4H), 1.71-1.58 (m, 4H), 1.56-0.84 (m,19H), 0.69 (s, 3H). LCMS Rt=0.813 min in 1.5 min chromatography, MS ESIcalcd. for C₂₇H₄₂N₂O₄Na [M+Na]⁺481, found 481.

Example 19. Synthesis of Compounds 40 and 41

To a solution of A1 (300 mg, 0.679 mmol) in acetone (4 mL) was addedK₂CO₃ (280 mg, 2.03 mmol) and 7-methoxy-2H-indazole (149 mg, 1.01 mmol).The mixture was stirred at 25° C. for 4 hrs. The solvent was removed byrotary evaporator. To the mixture was added water (5 mL) and EtOAc (6mL). The organic layer was separated. The aqueous phase was extractedwith EtOAc (2×6 mL). The combined organic layers was washed with brine(7 mL), dried over Na₂SO₄, filtered and concentrated to afford aresidue, which was purified by preparative HPLC to give compound 40(44.6 mg, 13%) and compound 41 (28.6 mg, 8%).

40: ¹H NMR (400 MHz, CDCl₃) δ 7.89 (s, 1H), 7.22 (d, J=8.5 Hz, 1H), 6.98(t, J=7.9 Hz, 1H), 6.54 (d, J=7.3 Hz, 1H), 5.27-5.14 (m, 2H), 3.99 (s,3H), 3.49-3.44 (m, 1H), 3.40-3.35 (m, 1H), 3.29 (s, 3H), 2.63 (t, J=8.7Hz, 1H), 2.26-2.00 (m, 3H), 1.78-1.66 (m, 5H), 1.51-1.06 (m, 16H),1.04-0.79 (m, 2H), 0.72 (s, 3H). LCMS Rt=1.345 min in 2 minchromatography, MS ESI calcd. for C₃₁H₄₅N₂O₄ [M+H]⁺ 509, found 509.

41: ¹H NMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.02(t, J=7.8 Hz, 1H), 6.68 (d, J=7.5 Hz, 1H), 5.49-5.42 (m, 1H), 5.37-5.30(m, 1H), 3.86 (s, 3H), 3.51-3.46 (m, 1H), 3.41-3.35 (m, 1H), 3.30 (s,3H), 2.61 (t, J=8.9 Hz, 1H), 2.25-2.01 (m, 3H), 1.79-1.61 (m, 6H),1.54-1.46 (m, 3H), 1.38-1.06 (m, 12H), 1.03-0.80 (m, 2H), 0.72 (s, 3H).LCMS Rt=1.374 min in 2 min chromatography, MS ESI calcd. for C₃₁H₄₅N₂O₄[M+H]⁺ 509, found 509.

Example 20. Synthesis of Compounds 42 and 43

To a solution of A1 (300 mg, 0.679 mmol) in acetone (4 mL) was addedK₂CO₃ (280 mg, 2.03 mmol) and 5-methoxy-2H-indazole (149 mg, 1.01 mmol).The mixture was stirred at 25° C. for 4 hrs. The solvent was removed byrotary evaporator. To the mixture was added water (5 mL) and EtOAc (6mL). The organic layer was separated. The aqueous phase was extractedwith EtOAc (2×6 mL). The combined organic layers was washed with brine(7 mL), dried over Na₂SO₄, filtered and evaporated to afford a residue,which was purified by preparative HPLC to give compound 42 (37.2 mg,11%) and compound 43 (71.6 mg, 21%).

42: ¹H NMR (400 MHz, CDCl₃) δ 7.79 (s, 1H), 7.59 (d, J=9.5 Hz, 1H), 6.99(dd, J=2.3, 9.5 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 5.23-5.07 (m, 2H), 3.83(s, 3H), 3.48 (s, 1H), 3.40-3.35 (m, 1H), 3.29 (s, 3H), 2.62 (t, J=8.8Hz, 1H), 2.28-2.17 (m, 1H), 2.13-1.98 (m, 2H), 1.80-1.61 (m, 5H),1.57-1.07 (m, 16H), 1.03-0.80 (m, 2H), 0.72 (s, 3H). LCMS Rt=1.333 minin 2 min chromatography, MS ESI calcd. for C₃₁H₄₅N₂O₄ [M+H]⁺ 509, found509.

43: ¹H NMR (400 MHz, CDCl₃) δ 7.94 (s, 1H), 7.13-7.02 (m, 3H), 5.15-5.03(m, 2H), 3.85 (s, 3H), 3.50-3.44 (m, 1H), 3.40-3.34 (m, 1H), 3.29 (s,3H), 2.62 (t, J=8.8 Hz, 1H), 2.27-1.99 (m, 3H), 1.80-1.61 (m, 5H),1.56-1.06 (m, 16H), 1.03-0.79 (m, 2H), 0.73 (s, 3H). LCMS Rt=1.347 minin 2 min chromatography, MS ESI calcd. for C₃₁H₄₅N₂O₄ [M+H]⁺ 509, found509.

Example 21. Synthesis of Compounds 44 and 45

To a solution of A1 (300 mg, 0.679 mmol) in acetone (4 mL) was addedK₂CO₃ (280 mg, 2.03 mmol) and 4-methoxy-2H-indazole (149 mg, 1.01 mmol).The mixture was stirred at 25° C. for 4 hrs. The solvent was removed byrotary evaporator. To the mixture was added water (5 mL) and EtOAc (6mL). The organic layer was separated. The aqueous phase was extractedwith EtOAc (2×6 mL). The combined organic layers was washed with brine(7 mL), dried over Na₂SO₄, filtered and evaporated to afford a residue,which was purified by preparative HPLC to give compound 44 (35.2 mg,10%) and compound 45 (65.5 mg, 19%).

44: ¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H), 7.28 (s, 1H), 7.23-7.15 (m,1H), 6.33 (d, J=7.3 Hz, 1H), 5.23-5.09 (m, 2H), 3.93 (s, 3H), 3.51-3.43(m, 1H), 3.40-3.35 (m, 1H), 3.29 (s, 3H), 2.63 (t, J=8.8 Hz, 1H),2.28-2.17 (m, 1H), 2.13-1.99 (m, 2H), 1.80-1.61 (m, 5H), 1.56-1.07 (m,16H), 1.04-0.79 (m, 2H), 0.72 (s, 3H). LCMS Rt=1.342 min in 2 minchromatography, MS ESI calcd. for C₃₁H₄₅N₂O₄ [M+H]⁺ 509, found 509.

45: ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.32-7.27 (m, 1H), 6.77 (d,J=8.5 Hz, 1H), 6.48 (d, J=7.5 Hz, 1H), 5.14-5.03 (m, 2H), 4.00-3.93 (m,3H), 3.50-3.44 (m, 1H), 3.40-3.34 (m, 1H), 3.29 (s, 3H), 2.62 (t, J=8.7Hz, 1H), 2.25-1.99 (m, 3H), 1.81-1.59 (m, 6H), 1.55-1.06 (m, 15H),1.04-0.79 (m, 2H), 0.73 (s, 3H). LCMS Rt=1.361 min in 2 minchromatography, MS ESI calcd. for C₃₁H₄₅N₂O₄ [M+H]⁺ 509, found 509.

Example 22. Synthesis of Compounds 46 and 47

To a solution of 2H-pyrazolo[3,4-c]pyridine (80.8 mg, 0.679 mmol) in THF(3 mL) was added NaH (32.4 mg, 1.35 mmol) at 25° C. The mixture wasstirred at 20° C. for 30 mins, then a solution of C1 (200 mg, 0.453mmol) in THF (2 mL) was added. The reaction mixture was stirred at 20°C. for 16 hrs. The mixture was quenched with water (10 mL), extractedwith EtOAc (2×15 mL). The combined organic phase was washed with brine(30 mL), dried over Na₂SO₄ and concentrated in vacuum. The residue waspurified by preparative TLC (eluted with EtOAc) to give compound 46 (9.9mg, 5%) and compound 47 (17.3 mg, 8%).

46: ¹H NMR (400 MHz, CDCl₃) δ 9.31 (s, 1H), 8.19 (d, J=6.0 Hz, 1H), 8.00(s, 1H), 7.62-7.52 (m, 1H), 5.38-5.18 (m, 2H), 3.54 (d, J=9.0 Hz, 1H),3.33 (s, 3H), 3.21 (d, J=9.0 Hz, 1H), 2.71-2.61 (m, 1H), 2.29-2.10 (m,2H), 1.98-1.60 (m, 9H), 1.50-1.27 (m, 11H), 1.22-1.09 (m, 2H), 0.91-0.76(m, 2H), 0.70 (s, 3H). LCMS Rt=1.039 min in 2 min chromatography, MS ESIcalcd. for C₂₉H₄₂N₃O₃ [M+H]⁺480, found 480.

47: ¹H NMR (400 MHz, CDCl₃) δ 8.79 (s, 1H), 8.34 (d, J=5.5 Hz, 1H), 8.10(s, 1H), 7.64 (dd, J=1.1, 5.6 Hz, 1H), 5.31-5.19 (m, 2H), 3.54 (d, J=9.0Hz, 1H), 3.34 (s, 3H), 3.22 (d, J=9.0 Hz, 1H), 2.71-2.63 (m, 1H),2.27-2.09 (m, 2H), 1.98-1.87 (m, 2H), 1.83-1.61 (m, 6H), 1.56-1.40 (m,8H), 1.37-1.27 (m, 6H), 1.22-1.10 (m, 2H), 0.71 (s, 3H). LCMS Rt=1.069min in 2 min chromatography, MS ESI calcd. for C₂₉H₄₂N₃O₃ [M+H]⁺480,found 480.

Example 23. Synthesis of Compound 48 and 49

To a solution of A1 (300 mg, 0.679 mmol) in acetone (4 mL) was addedK₂CO₃ (280 mg, 2.03 mmol) and 6-methoxy-2H-indazole (149 mg, 1.01 mmol).The mixture was stirred at 25° C. for 4 hrs. The solvent was removed byrotary evaporator. To the mixture was added water (5 mL) and EtOAc (6mL). The organic layer was separated. The aqueous phase was extractedwith EtOAc (2×6 mL). The combined organic layers was washed with brine(7 mL), dried over Na₂SO₄, filtered and concentrated to afford aresidue, which was purified by preparative HPLC to give compound 49 (3.3mg, 0.2%) and compound 48 (81.2 mg, 1%).

48: ¹H NMR (400 MHz, CDCl₃) δ7.82 (s, 1H), 7.52 (d, J=9.0 Hz, 1H), 6.94(s, 1H), 6.77 (dd, J=2.3, 9.0 Hz, 1H), 5.19-5.03 (m, 2H), 3.85 (s, 3H),3.50-3.44 (m, 1H), 3.40-3.34 (m, 1H), 3.29 (s, 3H), 2.62 (t, J=8.8 Hz,1H), 2.27-2.17 (m, 1H), 2.13-1.99 (m, 2H), 1.78-1.67 (m, 4H), 1.50-1.12(m, 16H), 1.02-0.81 (m, 3H), 0.72 (s, 3H). LCMS Rt=1.326 min in 2 minchromatography, MS ESI calcd. for C₃₁H₄₅N₂O₄ [M+H]⁺ 509, found 509.

49: ¹H NMR (400 MHz, CDCl₃) δ 7.93 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 6.81(dd, J=2.0, 8.8 Hz, 1H), 6.53 (s, 1H), 5.13-4.99 (m, 2H), 3.84 (s, 3H),3.51-3.44 (m, 1H), 3.41-3.34 (m, 1H), 3.29 (s, 3H), 2.63 (t, J=8.8 Hz,1H), 2.25-2.01 (m, 3H), 1.79-1.65 (m, 5H), 1.55-1.10 (m, 16H), 1.04-0.79(m, 2H), 0.74 (s, 3H). LCMS Rt=1.341 min in 2 min chromatography, MS ESIcalcd. for C₃₁H₄₅N₂O₄ [M+H]⁺ 509, found 509.

Example 24. Synthesis of Compound 50

To a solution of C1 (200 mg, 0.453 mmol) and 6-chloro-2H-indazole (103mg, 0.679 mmol) in acetone (5 mL) was added K₂CO₃ (93.8 mg, 0.679 mmol).The reaction mixture was stirred at 25° C. for 2 hrs. The reactionmixture was diluted with EtOAc (50 mL), washed with H₂O (20 mL), brine(20 mL), dried over Na₂SO₄, filtered and concentrated to afford crudeproduct, which was purified by preparative HPLC to give compound 50 (10mg, 5%).

50: ¹H NMR (400 MHz, CDCl₃) δ 8.03 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.22(s, 1H), 7.15 (d, J=8.5 Hz, 1H), 5.20-5.03 (m, 2H), 3.57 (d, J=9.0 Hz,1H), 3.36 (s, 3H), 3.23 (d, J=9.0 Hz, 1H), 2.65 (t, J=8.7 Hz, 1H),2.30-2.09 (m, 2H), 1.99-1.91 (m, 2H), 1.77-1.45 (m, 14H), 1.34-1.14 (m,8H), 0.73 (s, 3H). LCMS t_(R)=3.185 min in 4 min chromatography, MS ESIcalcd. for C₃₀H₄₂ClN₂O₃[M+H]⁺ 513, found 513.

Example 25. Synthesis of Compound 51

To a solution of A1 (200 mg, 0.47 mmol) in acetone (2 mL) was added5-chloro-4-fluoro-2H-benzo[d][1,2,3]triazole (0.116 g, 0.68 mmol),followed by K₂CO₃ (0.124 g, 0.906 mmol). The resulting reaction mixturewas stirred at 25° C. for 16 hrs. To the mixture was added water (4 mL)and extracted with EtOAc (3×2 mL). The combined organic phase wasconcentrated to give a residue, which was purified by preparative HPLCto give compound 51 (65.9 mg, 27%)

51: ¹H NMR (400 MHz, CDCl₃) δ 7.48 (dd, J=6.0, 8.8 Hz, 1H), 7.07 (d,J=7.6 Hz, 1H), 5.46-5.36 (m, 2H), 3.50-3.48 (m, 1H), 3.40-3.37 (m, 1H),3.30 (s, 3H), 2.72 (t, J=8.6 Hz, 1H), 2.30-2.01 (m, 3H), 1.80-1.70 (m,4H), 1.69-1.48 (m, 7H), 1.39-1.10 (m, 10H), 1.09-0.76 (m, 2H), 0.74 (s,3H). LCMS Rt=1.374 min in 2 min chromatography, MS ESI calcd. forC₂₉H₄₀ClFN₃O₃[M+H]⁺ 532, found 532.

Example 26. Synthesis of Compound 52

To a solution of C1 (100 mg, 0.226 mmol) in acetone (5 mL) was addedK₂CO₃ (62.4 mg, 0.452 mmol) and 5-fluoro-1H-imidazole (29.1 mg, 0.339mmol) at 15° C. The mixture was stirred at 45° C. for 12 h, then treatedwith water (20 mL) and extracted with EtOAc (2×30 mL). The organic phasewas washed with brine (30 mL), dried over anhydrous Na₂SO₄, andconcentrated in vacuum prior to being purified by preparative HPLC toafford compound 52 (18.3 mg) as an off-white solid.

52: ¹H NMR (400 MHz, CDCl₃) δ 7.00 (s, 1H), 6.37 (dd, J=1.2 Hz, 8.0 Hz,1H), 4.60-4.59 (m, 2H), 3.50 (d, J=8.8 Hz, 1H), 3.31 (s, 3H), 3.21 (d,J=8.8 Hz, 1H), 2.57-2.55 (m, 1H), 2.23-2.10 (m, 1H), 1.91-1.85 (m, 3H),1.80-1.1.65 (m, 6H), 1.64-1.14 (m, 16H), 0.65 (s, 3H). LCMS Rt=0.861 minin 1.5 min chromatography, MS ESI calcd. for C₂₆H₄₀FN₂O₃ [M+H]⁺ 447,found 447.

Example 27. Synthesis of Compound 53

To a solution of A1 (600 mg, 1.35 mmol) in 3 mL of acetone was added4-nitro-H-pyrazole (197 mg, 1.75 mmol) and K₂CO₃ (373 mg, 2.7 mmol) at25° C. After stirring at 55° C. for 3 hrs, the reaction mixture waspoured into ice-cold water, extracted with EtOAc (2×50 mL), washed withbrine (2×30 mL), dried over Na₂SO₄, filtered, and evaporated undervacuum to give 500 mg of the crude product, which was purified byprep-HPLC to obtain compound 53 (30.0 mg, 23%) as an off-white solid.

53: ¹H NMR (400 MHz, CDCl₃): δ 8.17 (s, 1H), 8.08 (s, 1H), 5.00-4.86 (m,2H), 3.48-3.44 (m, 1H), 3.37 (d, J=9.8 Hz, 1H), 3.28 (s, 3H), 2.61 (t,J=8.8 Hz, 1H), 2.26-2.18 (m, 1H), 2.03 (d, J=13.4 Hz, 2H), 1.77-1.69 (m,4H), 1.55-1.47 (m, 4H), 1.46-1.04 (m, 13H), 1.03-0.95 (m, 1H), 0.90-0.81(m, 1H), 0.69 (s, 3H). LCMS Rt=2.859 min in 4.0 min chromatography, MSESI calcd. for C₂₆H₃₈N₃O₄ [M−H₂O+H]⁺456, found 456.

Example 28. Synthesis of Compounds 54 and 55

Step 1. To a stirred solution of 53 (400 mg, 0.844 mmol) in 20 mL ofMeOH was added Pd/C (200 mg). The reaction was stirred under H₂ at 25°C. for 3 hrs, then the reaction mixture was filtered, washed with MeOH(20 mL) and evaporated under vacuum to give a crude product (300 mg),which was purified by HPLC to obtain compound 54 (15 mg, 90%) as anoff-white solid.

54: ¹H NMR ¹H NMR (400 MHz, DMSO-d₆): □ 10.00 (br. s., 2H), 7.90 (s,1H), 7.55 (s, 1H), 5.21-5.00 (m, 2H), 3.37-3.30 (m, 2H), 3.24-3.15 (m,3H), 2.77-2.62 (m, 2H), 2.33 (br. s., 1H), 2.04 (d, J=9.6 Hz, 2H),1.92-1.50 (m, 10H), 1.48-1.01 (m, 10H), 0.99-0.88 (m, 1H), 0.83-0.72 (m,1H), 0.64-0.47 (m, 3H). LCMS Rt=1.984 min in 4.0 min chromatography, MSESI calcd. for C₂₆H₄₂N₃O₃ [M+H]⁺ 444.2, found 444.2.

Step 2. To a stirred solution of compound 54 (200 mg, 0.450 mmol) in 5mL of DCM was added Ac₂O (45.9 mg, 0.450 mmol) and TEA (0.124 mL, 0.9mmol) and DMAP (109 mg, 0.9 mmol) at 25° C. After stirring at 25° C. for0.5 hrs, the reaction mixture was poured into water (20 mL), extractedwith EtOAc (2×50 mL), washed with brine (2×30 mL), dried over Na₂SO₄,filtered and evaporated in vacuum. The crude product was purified byprep-HPLC to obtain compound 55 (30.7 mg, 14%) as an off-white solid.

55: ¹H NMR (400 MHz, CDCl₃): δ 7.89 (brs, 1H), 7.42 (brs, 1H), 7.30(brs, 1H), 4.94-4.77 (m, 2H), 3.48-3.42 (m, 1H), 3.39-3.34 (m, 1H), 3.28(s, 3H), 2.57 (brs, 1H), 2.23-2.10 (m, 4H), 2.06-1.99 (m, 2H), 1.76-1.62(m, 9H), 1.51 (dd, J=12.6, 4.5 Hz, 3H), 1.33 (t, J=13.6 Hz, 2H),1.25-1.18 (m, 5H), 1.16-1.05 (m, 2H), 1.02-0.92 (m, 1H), 0.83 (t, J=9.6Hz, 1H), 0.68 (s, 3H). LCMS Rt=2.631 min in 4.0 min chromatography, MSESI calcd. for C₂₈H₄₄N₃O₄ [M+H]⁺486.3, found 486.3.

Example 29. Synthesis of Compound 56

To a stirred solution of C1 (90 mg, 0.203 mmol) in 3 mL of acetone wasadded 1H-imidazole-2-carbonitrile (24.4 mg, 0.263 mmol) and K₂CO₃ (56.1mg, 0.406 mmol) at 25° C. After stirring at 55° C. for 4 hrs, thereaction mixture was poured into ice-cold water, extracted with EtOAc(2×50 mL), washed with brine (2×30 mL), dried over Na₂SO₄, filtered andevaporated under vacuum. The crude product was purified by preparativeHPLC to obtain compound 56 (25.6 mg, 28%) as an off-white solid.

56: ¹H NMR (400 MHz, CDCl₃): δ 7.26 (s, 1H), 7.13-6.98 (m, 1H),5.02-4.79 (m, 2H), 3.57-3.50 (m, 1H), 3.33 (s, 3H), 3.20 (d, J=9.0 Hz,1H), 2.62 (br. s., 1H), 2.22 (d, J=8.6 Hz, 1H), 2.08 (d, J=10.6 Hz, 1H),1.92 (br. s., 2H), 1.79-1.57 (m, 11H), 1.52-1.42 (m, 4H), 1.29 (s, 5H),1.24-1.09 (m, 2H), 0.70 (s, 3H). LCMS Rt=2.553 min in 4.0 minchromatography, MS ESI calcd. for C₂₇H₄₀N₃O₃ [M+H]⁺ 454.3, found 454.3.

Example 30. Synthesis of Compound 57

To a stirred solution of C1 (80 mg, 0.181 mmol) in 3 mL of acetone wasadded 4-isopropoxy-1H-pyrazole (29.6 mg, 0.235 mmol) and K₂CO₃ (50 mg,0.362 mmol) at 25° C. After stirring at 55° C. for 4 hrs, the reactionmixture was poured into ice-cold water, extracted with EtOAc (2×50 mL,washed with brine (2×30 mL), dried over Na₂SO₄, filtered and evaporatedunder vacuum. The crude product was purified by preparative HPLC toobtain compound 57 (16.3 mg, 19%) as an off-white solid.

57: ¹H NMR (400 MHz, CDCl₃): δ 7.26 (s, 1H), 7.06 (s, 1H), 4.84-4.72 (m,2H), 4.17 (dt, J=12.2, 6.2 Hz, 1H), 3.54 (d, J=9.0 Hz, 1H), 3.32 (s,3H), 3.18 (d, J=9.0 Hz, 1H), 2.54 (t, J=8.8 Hz, 1H), 2.22-2.13 (m, 1H),2.03 (d, J=11.6 Hz, 1H), 1.91 (d, J=5.8 Hz, 2H), 1.80-1.66 (m, 4H),1.56-1.34 (m, 11H), 1.33-1.26 (m, 9H), 1.24 (br. s., 4H), 0.65 (s, 3H).LCMS Rt=2.758 min in 4.0 min chromatography, MS ESI calcd. forC₂₉H₄₇N₂O₄ [M+H]⁺ 487.4, found 487.4.

Example 31. Synthesis of Compound 58

To a stirred solution of C1 (80 mg, 0.181 mmol) in 3 mL of acetone wasadded 4-ethoxy-1H-pyrazole (26.3 mg, 0.235 mmol) and K₂CO₃ (50 mg, 0.362mmol) at 25° C. After stirring at 55° C. for 4 hrs, the reaction mixturewas poured into ice-cold water, extracted with EtOAc (2×50 mL), washedwith brine (2×30 mL), dried over Na₂SO₄, filtered and evaporated undervacuum. The crude product was purified by preparative HPLC to obtaincompound 58 (12.3 mg, Yield: 14%) as an off-white solid.

58: ¹H NMR (400 MHz, CDCl₃): δ 7.27 (br. s., 1H), 7.06 (s, 1H),4.86-4.70 (m, 2H), 3.94 (q, J=6.8 Hz, 2H), 3.58-3.49 (m, 1H), 3.32 (s,3H), 3.23-3.13 (m, 1H), 2.53 (t, J=8.4 Hz, 1H), 2.22-2.14 (m, 1H),2.07-1.97 (m, 2H), 1.91 (d, J=4.8 Hz, 2H), 1.79-1.59 (m, 7H), 1.51-1.33(m, 8H), 1.32-1.15 (m, 9H), 0.65 (s, 3H). LCMS Rt=2.686 min in 4.0 minchromatography, MS ESI calcd. for C₂₈H₄₅N₂O₄ [M+H]⁺ 473.3, found 473.3.

Example 32. Synthesis of Compound 59

To a solution of A1 (100 mg, 226 μmol) in acetone (5 mL) was added K₂CO₃(62.4 mg, 452 μmol) and 5-fluoro-1H-imidazole (23.3 mg, 271 μmol) at 55°C. The mixture was stirred at 55° C. for 12 hrs, at which point H₂O (10mL) was added. The mixture was extracted with EtOAc (2×20 mL), and thecombined organic layer was washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a crudeproduct, which was purified by preparative HPLC to afford compound 59(22 mg, 22%) as an off-white solid.

59: ¹H NMR (400 MHz, CDCl₃) δ 7.02 (s, 1H), 6.39 (dd, J=1.8, 8.0 Hz,1H), 4.69-4.54 (m, 2H), 3.53-3.36 (m, 2H), 3.31 (s, 3H), 2.59 (t, J=8.9Hz, 1H), 2.30-2.16 (m, 1H), 2.09-2.00 (m, 1H), 1.99-1.91 (m, 1H),1.82-1.68 (m, 4H), 1.67-1.61 (m, 2H), 1.56-1.45 (m, 3H), 1.45-1.30 (m,3H), 1.29-1.20 (m, 6H), 1.19-1.09 (m, 3H), 1.06-0.82 (m, 2H), 0.70 (s,3H). LCMS Rt=0.992 min in 2 min chromatography, MS ESI calcd. forC₂₆H₄₀FN₂O₃[M+H]⁺ 447, found 447.

Example 33. Synthesis of Compound 60

To a solution of A1 (200 mg, 0.453 mmol) in acetone (5 mL) was addedK₂CO₃ (93.8 mg, 0.679 mmol) and 4-methyl-1H-pyrazole (44.5 mg, 0.543mmol) at 50° C. The mixture was stirred at 50° C. for 12 hrs, thenpoured into water (10 mL) and extracted with EtOAc (2×20 mL). Thecombined organic layer was washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the crudeproduct, which was purified by preparative HPLC to give compound 60 (107mg, 53%) as an off-white solid.

60: ¹H NMR (400 MHz, CDCl₃) δ 7.38 (s, 1H), 7.20 (s, 1H), 4.97-4.82 (m,2H), 3.51-3.35 (m, 2H), 3.30 (s, 3H), 2.63-2.55 (m, 1H), 2.28-2.16 (m,1H), 2.12 (s, 3H), 2.08-2.00 (m, 2H), 1.79-1.66 (m, 5H), 1.63-1.56 (m,3H), 1.53-1.47 (m, 3H), 1.42-1.30 (m, 2H), 1.27-1.19 (m, 6H), 1.18-1.07(m, 2H), 1.05-0.92 (m, 1H), 0.91-0.80 (m, 1H), 0.71 (s, 3H). LCMSRt=1.028 min in 2 min chromatography, MS ESI calcd. for C₂₇H₄₃N₂O₃[M+H]⁺ 443, found 443.

Example 34. Synthesis of Compound 61

To a solution of A1 (80 mg, 0.181 mmol) in acetone (3 mL) was added4-ethoxy-1H-pyrazole (30.3 mg, 0.271 mmol) and K₂CO₃ (49.9 mg, 0.362mmol) at 15° C. The mixture was stirred at 40° C. for 15 hrs, then wasdiluted with DCM (10 mL) and filtered. The filtrate was concentrated toget the crude product, which was purified by preparative HPLC to affordcompound 61 (17.6 mg, 21%).

61: ¹H NMR (400 MHz, CD₃OD) δ 7.30 (s, 1H), 7.24 (s, 1H), 4.64 (br. s.,2H), 3.96 (q, J=7.0 Hz, 2H), 3.54-3.40 (m, 2H), 3.31 (s, 3H), 2.72-2.64(m, 1H), 2.22-1.94 (m, 5H), 1.82-1.12 (m, 19H), 1.09-0.81 (m, 4H), 0.71(s, 3H). LCMS Rt=1.840 min in 3.0 min chromatography, MS ESI calcd. forC₂₈H₄₅N₂O₄ [M+H]⁺ 473, found 473.

Example 35. Synthesis of Compounds 62 and 63

Step 1. To a solution of D1 (2 g, 6.01 mmol) in 40 mL of anhydrousdichloromethane was added PCC (2.58 g, 12 mmol) at 25° C. The mixturewas stirred at 25° C. for 2 hrs. The solution was filtered and thefilter cake was washed with DCM (2×50 mL). The combined filtrate wasconcentrated in vacuum. The residue was purified by silica gel columneluted with (PE/EtOAc=10/1) to afford D2 (1.6 g 77%) as an off-whitesolid.

D2: ¹H NMR (400 MHz, CDCl₃) δ 9.75 (s, 1H), 5.17-5.08 (m, 1H), 2.42-2.28(m, 2H), 2.26-2.12 (m, 1H), 2.04-1.80 (m, 3H), 1.78-1.67 (m, 1H),1.67-1.59 (m, 6H), 1.58-1.45 (m, 6H), 1.40-1.33 (m, 3H), 1.32-1.25 (m,4H), 1.24-1.07 (m, 3H), 0.93 (s, 3H).

Step 2. To a solution of D2 (1.2 g, 3.63 mmol) in MeOH (10 mL) and THF(10 mL) was added NaBD₄ (227 mg, 5.44 mmol) at 25° C. The reactionmixture was stirred at 25° C. for 2 hrs. The reaction was poured intowater (100 mL) and extracted with (2×50 mL). The combined organic layerwas washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated in vacuum to afford D3 (1.1 g, crude) as an off-whitesolid.

D3: ¹H NMR (400 MHz, CDCl₃) δ 5.18-5.06 (m, 1H), 3.54-3.48 (m, 1H),2.41-2.31 (m, 1H), 2.29-2.11 (m, 2H), 2.01-1.84 (m, 2H), 1.82-1.71 (m,1H), 1.67-1.59 (m, 5H), 1.54-1.34 (m, 5H), 1.33-1.08 (m, 12H), 0.85 (s,3H).

Step 3. To a solution of D3 (1 g, 2.99 mmol) in DMF (15 mL) was addedNaH (358 mg, 8.97 mmol, 60%) at 25° C. The mixture was stirred at 25° C.for 30 mins. Me₂SO₄ (377 mg, 2.99 mmol, 100 mg/mL in THF) was added andthe reaction mixture was stirred at 25° C. for 12 h. The mixture waspoured into ice water (20 mL) and extracted with EtOAc (2×30 mL). Thecombined organic phase was washed with brine (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by column chromatography on silica gel (PE/EtOAc=10/1) toafford D4 (506 mg, 44%) as a colorless oil.

D4: ¹H NMR (400 MHz, CDCl₃) δ 5.19-5.00 (m, 1H), 3.36 (s, 3H), 2.44-2.12(m, 3H), 2.02-1.88 (m, 2H), 1.85-1.71 (m, 1H), 1.66-1.40 (m, 10H),1.41-1.12 (m, 12H), 0.96-0.82 (m, 5H).

Step 4. To a solution of D4 (506 mg, 1.45 mmol) in THF (3 mL) was addeddrop wise a solution of BH₃-Me₂S (1.44 mL, 14.4 mmol) at 0° C. Thesolution was stirred at 25° C. for 16 hrs. After cooling to 0° C., asolution of NaOH (4.8 mL, 3M) was added very slowly. After the addition,H₂O₂ (3 mL, 33%) was added slowly and the inner temperature wasmaintained below 10° C. The resulting solution was stirred at 25° C. for2 hrs. The resulting solution was extracted with EtOAc (2×20 mL). Thecombined organic layer was washed with saturated Na₂S₂O₃ (2×50 mL),brine (50 mL), dried over Na₂SO₄, filtered and concentrated in vacuum togive D5 (410 mg, crude) as an off-white solid, which was used for thenext step without further purification.

D5: ¹H NMR (400 MHz, CDCl₃) δ 3.78-3.72 (m, 1H), 3.35 (s, 3H), 3.18 (m,1H), 1.96-1.94 (m, 3H), 1.59-1.45 (m, 11H), 1.29-1.10 (m, 16H),0.88-0.75 (m, 1H), 0.75-0.56 (m, 3H).

Step 5. To a solution of D5 (410 mg, 1.12 mmol) in THF (2 mL) and DCM (8mL) was added PCC (481 mg, 2.24 mmol) at 25° C. The mixture was stirredat 25° C. for 2 hrs. The solution was filtered and the filter cake waswashed with DCM (2×50 mL). The combined filtrate was concentrated invacuum, and the residue was purified by silica gel column eluted with(PE/EtOAc=6/1) to afford D6 (242 mg, 56%) as an off-white solid.

D6: ¹H NMR (400 MHz, CDCl₃) δ 3.52-3.15 (m, 4H), 2.52 (t, J=8.9 Hz, 1H),2.20-2.08 (m, 4H), 2.04-1.84 (m, 3H), 1.81-1.60 (m, 4H), 1.55-1.34 (m,8H), 1.31-1.05 (m, 10H), 0.60 (s, 3H).

Step 6. To a solution of D6 (242 mg, 0.665 mmol) and HBr (0.05 mL, 48%in water) in MeOH (5 mL) was added bromine (127 mg, 0.798 mmol). Thereaction mixture was stirred at 25° C. for 2 hrs. The reaction wasquenched by saturated NaHCO₃ (20 mL) and pH was adjusted to 7-8. Themixture was extracted with EtOAc (2×30 mL). The combined organic layerswas washed with brine (50 mL), dried over Na₂SO₄ filtered andconcentrated in vacuum. The residue was purified by silica gel columneluted with (PE/EtOAc=10/1) to afford D7 (180 mg, 58%) as an off-whitesolid.

D7: ¹H NMR (400 MHz, CDCl₃) δ 3.95-3.85 (m, 2H), 3.52-3.14 (m, 4H),2.85-2.77 (m, 1H), 2.24-2.10 (m, 1H), 1.96-1.85 (m, 3H), 1.81-1.66 (m,3H), 1.57-1.35 (m, 6H), 1.31-1.09 (m, 11H), 0.92-0.81 (m, 2H), 0.62 (s,3H).

Step 7. To a solution of D7 (180 mg, 0.406 mmol) in acetone (3 mL) wasadded K₂CO₃ (112 mg, 0.812 mmol) and 5-methyl-2H-tetrazole (84.9 mg,1.01 mmol). The mixture was stirred at 25° C. for 12 hrs. The mixturewas poured into water (30 mL) and extracted with EtOAc (2×30 mL). Thecombined organic layers was washed with brine (20 mL), dried overNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bypreparative HPLC to give compounds 62 (40 mg, 22%) and 63 (33 mg, 18%)as an off-white solid.

62: ¹H NMR (400 MHz, CDCl₃) δ 5.34 (s, 2H), 3.52-3.19 (m, 4H), 2.65-2.59(m, 1H), 2.57 (s, 3H), 2.28-2.15 (m, 1H), 2.10-2.05 (m, 1H), 1.98-1.87(m, 2H), 1.84-1.70 (m, 3H), 1.67-1.62 (m, 1H), 1.60-1.40 (m, 8H),1.37-1.09 (m, 10H), 0.70 (s, 3H). LCMS Rt=0.979 min in 2.0 minchromatography, MS ESI calcd. for C₂₅H₃₈DN₄O₂[M+H—H₂O]⁺428, found 428.

63: ¹H NMR (400 MHz, CDCl₃) δ 5.19-5.01 (m, 2H), 3.50-3.20 (m, 4H),2.69-2.61 (m, 1H), 2.47 (s, 3H), 2.26-2.14 (m, 1H), 2.10-2.05 (m, 1H),1.98-1.87 (m, 2H), 1.85-1.71 (m, 3H), 1.68-1.62 (m, 2H), 1.61-1.59 (m,1H), 1.57-1.41 (m, 7H), 1.39-1.10 (m, 9H), 0.67 (s, 3H). Rt=0.897 min in2.0 min chromatography, MS ESI calcd. for C₂₅H₃₈DN₄O₂[M+H—H₂O]⁺428,found 428.

Example 36. Synthesis of Compound 64

To a solution of C1 (110 mg, 249 μmol) in acetone (5 mL) was added K₂CO₃(51.5 mg, 373 μmol) and 2-methyl-1H-imidazole (24.4 mg, 298 μmol) at 25°C. The mixture was stirred at 25° C. for 2 hrs. The mixture was pouredinto water (10 mL) and extracted with EtOAc (2×20 mL). The combinedorganic layer was washed with brine (10 mL), dried over Na₂SO₄ filteredand concentrated under reduced pressure to give the crud product, whichwas purified by HPLC to give compound 64 (9.5 mg, 9%) as an off-whitesolid.

64: ¹H NMR (400 MHz, DMSO-d6) δ 6.86 (s, 1H), 6.70 (s, 1H), 4.98-4.69(m, 2H), 3.47 (d, J=9.3 Hz, 1H), 3.20 (s, 3H), 3.15 (d, J=9.0 Hz, 1H),2.67 (m, 1H), 2.07 (s, 3H), 2.02-1.56 (m, 7H), 1.56-1.32 (m, 8H),1.32-0.96 (m, 11H), 0.53 (s, 3H). LCMS Rt=0.742 min in 2.0 minchromatography, MS ESI calcd. for C₂₇H₄₃N₂O₃ [M+H]⁺ 443, found 443.

Example 37. Synthesis of Compounds 65 and 66

Step 1. To a solution of C1 (450 mg, 1.01 mmol) in acetone (20 mL) wasadded K₂CO₃ (208 mg, 1.51 mmol) and 4-nitro-1H-pyrazole (136 mg, 1.21mmol) at 25° C. The mixture was stirred at 25° C. for 2 hrs. The mixturewas poured into water (10 mL) and extracted with EtOAc (2×20 mL). Thecombined organic layer was washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the crudeproduct (450 mg), of which 150 mg which was purified by preparative HPLCto give compound 65 (36.9 mg, 7%) as an off-white solid.

65: ¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 8.10 (s, 1H), 5.04-4.88 (m,2H), 3.55 (d, J=8.8 Hz, 1H), 3.35 (s, 3H), 3.23 (d, J=9.2 Hz, 1H),2.68-2.58 (m, 1H), 2.29-2.18 (m, 1H), 2.12-2.02 (m, 1H), 1.97-1.89 (m,2H), 1.85-1.73 (m, 3H), 1.71-1.59 (m, 3H), 1.56-1.44 (m, 7H), 1.40-1.15(m, 9H), 0.69 (s, 3H). LCMS Rt=1.030 min in 2.0 min chromatography, MSESI calcd. for C₂₆H₃₈N₃O₄ [M+H—H₂O]⁺456, found 456.

Step 2. To a solution of 65 (300 mg, 633 μmol) in MeOH (5 mL) was addedPd/C (10%, 300 mg) under N₂. The suspension was degassed under vacuumand purged with H₂ several times. The mixture was stirred under H₂ (15psi) at 25° C. for 12 hrs. The reaction mixture was filtered andconcentrated under reduced pressure to give the crude product (300 mg),150 mg of which was purified by preparative HPLC to give 66 (17 mg, 6%)as an off-white solid.

66: ¹H NMR (400 MHz, DMSO-d₆) δ 6.97 (s, 1H), 6.92 (s, 1H), 4.90-4.72(m, 2H), 4.25 (s, 1H), 3.84 (br. s., 2H), 3.49 (d, J=9.2 Hz, 1H), 3.25(s, 3H), 3.17 (d, J=9.2 Hz, 1H), 2.62-2.54 (m, 1H), 2.08-1.96 (m, 2H),1.88-1.73 (m, 3H), 1.72-1.56 (m, 3H), 1.55-1.44 (m, 4H), 1.43-1.32 (m,4H), 1.30-1.00 (m, 9H), 0.55 (s, 3H). LCMS Rt=0.604 min in 2.0 minchromatography, MS ESI calcd. for C26H₄₁N₃O₃Na [M+Na]⁺466, found 466.

Example 38. Synthesis of Compound 67

To a solution of C1 (110 mg, 249 μmol) in acetone (5 mL) was added K₂CO₃(51.5 mg, 373 μmol) and 4-(trifluoromethyl)-1H-pyrazole (40.5 mg, 298μmol) at 25° C. The mixture was stirred at 25° C. for 2 hrs. The mixturewas poured into water (10 mL) and extracted with EtOAc (2×20 mL), andthe combined organic layer was washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give thecrud product, which was purified by HPLC to give 67 (33.8 mg, 27%) as anoff-white solid.

67: ¹H NMR (400 MHz, CDCl₃) δ 7.74 (s, 2H), 5.06-4.86 (m, 2H), 3.56 (d,J=9.2 Hz, 1H), 3.35 (s, 3H), 3.22 (d, J=8.8 Hz, 1H), 2.66-2.57 (m, 1H),2.28-2.03 (m, 2H), 1.98-1.90 (m, 2H), 1.84-1.72 (m, 3H), 1.57-1.39 (m,9H), 1.38-1.10 (m, 10H), 0.69 (s, 3H). LCMS Rt=1.083 min in 2.0 minchromatography, MS ESI calcd. for C₂₇H₄₀F₃N₂O₃[M+H]⁺ 497, found 497.

Example 39. Synthesis of Compounds 68, 69, and 70

Step 1. To a mixture of propan-2-ol (27.7 g, 462 mmol) and TEA (46.6 g,462 mmol) in DCM (100 mL) was added sulfurous dichloride (25 g, 210mmol) dropwise at 0° C. The reaction mixture was stirred at 70° C. for 3hrs. The reaction mixture was cooled to 15° C., washed with water (2×200mL), brine (200 mL), dried over Na₂SO₄, filtered and evaporated to givediisopropyl sulfite (28.0 g, crude) as a brown oil. ¹H NMR (400 MHz,CDCl₃) δ 4.82-4.73 (m, 2H), 1.38-1.26 (m, 12H).

Step 2. To a solution of diisopropyl sulfite (24 g, 144 mmol) in CCl₄(20 mL), MeCN (20 mL) and water (30 mL) was added sodium periodate (92.4g, 432 mmol) in portions followed by ruthenium(III) chloride (8.96 mg,43.2 mmol) at 15° C. The reaction mixture was stirred at 15° C. for 1 h.The reaction mixture was filtered. The filtered cake was washed withEtOAc (4×250 mL). The organic layer was separated and washed with water(220 mL), saturated Na₂S₂O₃ (3×220 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum to give diisopropyl sulfate (26 g, 99%) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 4.88 (sept, J=6.4 Hz, 2H), 1.42(d, J=6.4 Hz, 12H).

Step 3. NaH (251 mg, 6.30 mmol) was added to a solution of D1 (300 mg,1.05 mmol) in THF (35 mL) at 0° C. under nitrogen. After that,diisopropyl sulfate (765 mg, 4.20 mmol) was added portion wise. Themixture was slowly warmed to room temperature and heated to 65° C. Thereaction mixture was stirred at 65° C. for 2 hrs. The mixture wasdiluted with water (200 mL) and extracted with EtOAc (3×200 mL). Thecombined organic layers were washed with saturated NH₄Cl (100 mL), driedwith anhydrous sodium sulfate and filtered. The solvents were removedunder reduced pressure and the residue was purified by columnchromatography on silica gel (PE/EtOAc=4/1) to afford D8 (300 mg, 76%)as an off-white solid.

D8: ¹H NMR (400 MHz, CDCl₃) δ 5.10 (q, J=6.8 Hz, 1H), 3.58 (d, J=9.2 Hz,1H), 3.47-3.41 (m, 1H), 3.21 (d, J=9.2 Hz, 1H), 2.41-2.29 (m, 1H),2.28-2.09 (m, 2H), 2.00-1.85 (m, 2H), 1.83-1.70 (m, 1H), 1.68-1.38 (m,14H), 1.37-1.16 (m, 9H), 1.13 (d, J=6.0 Hz, 6H), 0.85 (s, 3H).

Step 4. To a solution of D8 (380 mg, 1.01 mmol) in THF (15 mL) was addeddropwise a solution of BH₃-Me₂S (1.01 mL, 10 M, 10.1 mmol) at 0° C. Thesolution was stirred at 25° C. for 12 hrs. After cooling to 0° C., NaOHaqueous (3.36 mL, 3M, 10.1 mmol) was added slowly. After the addition,hydrogen peroxide (1.03 g, 33% w/w in water, 10.1 mmol) was added slowlyand the inner temperature maintained below 10° C. The resulting solutionwas stirred at 25° C. for 2 hrs. The resulting solution was extractedwith EtOAc (3×80 mL). The combined organic solution was washed withsaturated Na₂S₂O₃ (2×80 mL), brine (30 mL), dried over Na₂SO₄, filtered,and concentrated in vacuum to give D9 (401 mg, crude) as a white solid,which was used for the next step without further purification.

Step 5. To a solution of D9 (401 mg, 1.02 mmol) in DCM (30 mL) was addedPCC (393 mg, 1.83 mmol) and MgSO₄ (612 mg, 5.10 mmol) at 15° C. Thereaction mixture was stirred at 15° C. for 4 hrs. The reaction mixturewas filtered. The filtrate was concentrated under vacuum to give aresidue, which was purified by silica gel chromatography (PE/EtOAc=4/1)to afford D10 (280 mg, 70%) as an off-white solid.

D10: ¹H NMR (400 MHz, CDCl₃) δ 3.59-3.51 (m, 1H), 3.49-3.41 (m, 1H),3.22-3.19 (m, 1H), 2.53 (t, J=8.8 Hz, 1H), 2.20-2.08 (m, 4H), 2.05-1.95(m, 1H), 1.94-1.85 (m, 2H), 1.82-1.70 (m, 2H), 1.69-1.40 (m, 10H),1.39-1.16 (m, 10H), 1.13 (d, J=6.0 Hz, 6H), 0.60 (s, 3H).

Step 6. To a solution of D10 (150 mg, 384 μmol) in MeOH (20 mL) wasadded HBr (1 drop, 48% w/w in water) at 15° C. Liquid bromine (67.4 mg,422 μmol) was added at 15° C. The reaction mixture was stirred at 15° C.for 2 hrs. The mixture was quenched by saturated NaHCO₃ aqueous (20 mL)at 0° C. The mixture was extracted with EtOAc (3×80 mL), and thecombined organic phase was washed with water (100 mL), brine (100 mL),dried over Na₂SO₄, filtered, and evaporated under vacuum to give aresidue, which was purified by silica gel chromatography (PE/EtOAc=5/1)to afford D11 (220 mg, impure) as an off-white solid.

D11: ¹H NMR (400 MHz, CDCl₃) δ 3.96-3.83 (m, 2H), 3.53 (d, J=8.8 Hz,1H), 3.45 (m, 1H), 3.21 (d, J=8.8 Hz, 1H), 2.81 (t, J=8.8 Hz, 1H),2.24-2.09 (m, 1H), 1.98-1.85 (m, 3H), 1.82-1.67 (m, 3H), 1.65-1.31 (m,11H), 1.29-1.16 (m, 8H), 1.12 (d, J=6.0 Hz, 6H), 0.63 (s, 3H).

Step 7. To a solution of D11 (145 mg, 0.3088 mmol) in acetone (10 mL)was added 4,5-difluoro-2H-benzo[d][1,2,3]triazole (71.8 mg, 0.4632mmol), followed by K₂CO₃ (85.2 mg, 0.6176 mmol) at 15° C. The reactionmixture was stirred at 15° C. for 16 hrs, and the organic phase waswashed with water (2×100 mL), brine (120 mL), dried over Na₂SO₄,filtered, concentrated under vacuum to give a residue, which waspurified by preparative HPLC to afford 68 (37.7 mg, 22%), 69 (4.6 mg,3%) and 70 (20.8 mg, 12%).

68: ¹H NMR (400 MHz, CDCl₃) δ 7.45-7.30 (m, 1H), 7.10-7.00 (m, 1H),5.49-5.33 (m, 2H), 3.54 (d, J=8.8 Hz, 1H), 3.49-3.45 (m, 1H), 3.25 (d,J=8.8 Hz, 1H), 2.76-2.66 (m, 1H), 2.28-2.09 (m, 2H), 1.99-1.87 (m, 2H),1.85-1.71 (m, 3H), 1.69-1.34 (m, 11H), 1.34-1.16 (m, 8H), 1.14 (d, J=6.0Hz, 6H), 0.71 (s, 3H). LCMS R_(t)=4.647 min in 7 min chromatography, MSESI calcd. For C₃₁H₄₂F₂N₃O₂[M+H—H₂O]⁺526, found 526.

69: ¹H NMR (400 MHz, CDCl₃) δ 7.85-7.75 (m, 1H), 7.25-7.15 (m, 1H),5.57-5.47 (m, 2H), 3.54 (d, J=8.8 Hz, 1H), 3.49-3.45 (m, 1H), 3.25 (d,J=8.8 Hz, 1H), 2.70-2.62 (m, 1H), 2.29-2.09 (m, 2H), 1.99-1.86 (m, 2H),1.84-1.69 (m, 3H), 1.69-1.17 (m, 19H), 1.14 (d, J=6.0 Hz, 6H), 0.74 (s,3H). LCMS R_(t)=4.835 min in 7 min chromatography, MS ESI calcd. forC₃₁H₄₄F₂N₃O₃ [M+H]⁺ 544, found 544.

70: ¹H NMR (400 MHz, CDCl₃) δ 7.70-7.60 (m, 1H), 7.35-7.27 (m, 1H),5.60-5.44 (m, 2H), 3.54 (d, J=9.2 Hz, 1H), 3.49-3.45 (m, 1H), 3.25 (d,J=9.2 Hz, 1H), 2.70-2.62 (m, 1H), 2.29-2.09 (m, 2H), 1.99-1.86 (m, 2H),1.84-1.69 (m, 3H), 1.69-1.17 (m, 19H), 1.14 (d, J=6.0 Hz, 6H), 0.74 (s,3H). LCMS R_(t)=5.104 min in 7 min chromatography, MS ESI calcd. forC₃₁H₄₂F₂N₃O₂[M+H—H₂O]⁺526, found 526.

Example 40. Synthesis of Compounds 71 and 72

To a solution of D11 (170 mg, 0.3620 mmol) in acetone (15 mL) was added2H-tetrazole (38.0 mg, 0.543 mmol), followed by K₂CO₃ (99.9 mg, 0.724mmol) at 15° C. The reaction mixture was stirred at 15° C. for 16 hrs.The reaction mixture was diluted with DCM (80 mL), washed with water(3×50 mL), brine (60 mL), dried over Na₂SO₄, filtered and concentratedunder vacuum to give a solid, which was purified by preparative HPLC togive 71 (33 mg, 20%) as a white solid and crude 72 (45 mg, impure) whichwas further purified by silica gel chromatography (PE:EtOAc=3:1) to give72 (13 mg, 8%) as an off-white solid.

71: ¹H NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H), 5.38-5.12 (m, 2H), 3.52 (d,J=8.8 Hz, 1H), 3.50-3.40 (m, 1H), 3.24 (d, J=8.8 Hz, 1H), 2.66 (t, J=8.4Hz, 1H), 2.30-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.97-1.86 (m, 2H),1.85-1.71 (m, 3H), 1.69-1.41 (m, 10H), 1.40-1.16 (m, 9H), 1.13 (d, J=6.0Hz, 6H), 0.66 (s, 3H). LCMS R_(t)=3.394 min in 7 min chromatography, MSESI calcd. for C₂₆H₄₁N₄O₂ [M+H—H₂O]⁺441, found 441.

72: ¹H NMR (400 MHz, CDCl₃) δ 8.57 (s, 1H), 5.45 (s, 2H), 3.53 (d, J=9.0Hz, 1H), 3.50-3.40 (m, 1H), 3.24 (d, J=9.0 Hz, 1H), 2.69-2.59 (m, 1H),2.27-2.15 (m, 1H), 2.15-2.00 (m, 1H), 1.99-1.86 (m, 2H), 1.85-1.70 (m,3H), 1.68-1.33 (m, 13H), 1.33-1.18 (m, 6H), 1.13 (d, J=6.0 Hz, 6H), 0.71(s, 3H). LCMS R_(t)=3.670 min in 7 min chromatography, MS ESI calcd. forC₂₆H₄₁N₄O₂ [M+H—H₂O]⁺441, found 441.

Example 41. Synthesis of Compounds 73 and 74

Step 1. To a solution of D7 (3 g, 8.99 mmol) in DCM (50 mL) was addedPCC (3.84 g, 17.9 mmol) at 25° C. The mixture was stirred at 25° C. for2 hrs. The solution was filtered and the filter cake was washed with DCM(2×50 mL). The combined filtrate was concentrated in vacuum. The residuewas purified by silica gel column eluted with (PE/EtOAc=8/1) to affordD12 (2.7 g, 86%, D/H=7/1) as an off-white solid.

D12: ¹H NMR (400 MHz, CDCl₃) δ 9.75 (s, 0.14H), 5.16-5.10 (m, 1H),2.44-2.26 (m, 2H), 2.24-2.11 (m, 1H), 2.03-1.77 (m, 4H), 1.75-1.63 (m,6H), 1.59-1.45 (m, 6H), 1.40-1.26 (m, 7H), 1.24-1.08 (m, 3H), 0.93 (s,3H).

Step 2. To a solution of D12 (2.7 g, 8.14 mmol) in MeOH (20 mL) and THF(20 mL) was added NaBD₄ (510 mg, 12.2 mmol) at 25° C. The reactionmixture was stirred at 25° C. for 2 hrs. The reaction was poured intowater (100 mL) and extracted with EtOAc (2×100 mL). The combined organiclayer was washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated in vacuum to afford D13 (2.6 g, crude, D/H=7/1) as anoff-white solid.

D13: ¹H NMR (400 MHz, CDCl₃) δ 5.16-5.12 (m, 1H), 2.39-2.29 (m, 1H),2.28-2.25 (m, 2H), 1.98-1.95 (m, 2H), 1.67-1.66 (m, 1H), 1.65-1.64 (m,6H), 1.63-1.52 (m, 6H), 1.52-1.21 (m, 12H), 0.87 (s, 3H).

Step 3. To a solution of D13 (2.6 g, 7.77 mmol) in DCM (40 mL) was addedPCC (3.33 g, 15.5 mmol) at 25° C. The mixture was stirred at 25° C. for2 hrs. The solution was filtered and the filter cake was washed with DCM(2×50 mL). The combined filtrate was concentrated in vacuum. The residuewas purified by silica gel column eluted with (PE/EtOAc=8/1) to affordD14 (2.2 g, 81%, D/H=40/1) as an off-white solid.

D14: ¹H NMR (400 MHz, CDCl₃) δ 9.77 (s, 0.024H), 5.18-5.13 (m, 1H),2.43-2.36 (m, 3H), 1.97-1.94 (m, 4H), 1.69-1.61 (m, 12H), 1.56-1.49 (m,7H), 1.33-1.21 (m, 3H), 0.95 (s, 3H).

Step 4. To a solution of D14 (2.2 g, 6.63 mmol, D/H=40/1)) in MeOH (20mL) and THF (20 mL) was added NaBD₄ (416 mg, 9.94 mmol) at 25° C. Thereaction mixture was stirred at 25° C. for 2 hrs. The reaction waspoured into water (100 mL) and extracted with EtOAc (2×50 mL). Thecombined organic layer was washed with brine (50 mL), dried over Na₂SO₄,filtered and concentrated in vacuum to afford D15 (1.8 g, crude) as anoff-white solid.

D15: ¹H NMR (400 MHz, CDCl₃) δ 5.13-5.10 (m, 1H), 2.38-2.23 (m, 3H),1.95-1.92 (m, 2H), 1.64-1.63 (m, 1H), 1.62-1.50 (m, 12H), 1.47-1.19 (m,12H), 0.84 (s, 3H).

Step 5. To a solution of D15 (1.8 g, 5.38 mmol) in DMF (20 mL) was addedNaH (643 mg, 16.1 mmol, 60%) at 25° C. The mixture was stirred at 25° C.for 30 min. Me2SO₄ (678 mg, 5.38 mmol) was added to the mixture. Thereaction mixture was stirred at 25° C. for 12 hrs. The mixture waspoured into ice water (50 mL) and extracted with EtOAc (2×50 mL). Thecombined organic phase was washed with saturated brine (50 mL), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residuewas purified by column chromatography on silica gel (PE/EtOAc=10/1) toafford D16 (800 mg, 34%) as colorless oil.

D16: ¹H NMR (400 MHz, CDCl₃) δ 5.13-5.08 (m, 1H), 3.33 (s, 3H),2.32-2.23 (m, 3H), 1.92-1.91 (m, 2H), 1.65-1.64 (m, 1H), 1.57-1.48 (m,8H), 1.45-1.22 (m, 15H), 0.85 (s, 3H).

Step 6. To a solution of D16 (800 mg, 2.29 mmol) in THF (10 mL) wasadded drop wise a solution of BH₃-Me₂S (2.29 mL, 22.9 mmol) at 0° C. Thesolution was stirred at 25° C. for 16 hrs. After cooling to 0° C., asolution of NaOH (7.63 mL, 3M) was added very slowly. After the additionwas complete, H₂O₂ (4.7 mL, 33%) was added slowly and the innertemperature was maintained below 10° C. The resulting solution wasstirred at 25° C. for 2 hrs. The resulting solution was extracted withEtOAc (2×20 mL). The combined organic layer was washed with saturatedaqueous Na₂S₂O₃ (2×50 mL), brine (50 mL), dried over Na₂SO₄, filteredand concentrated in vacuum to give D17 (780 mg, crude) as an off-whitesolid. The crude product was used for the next step without furtherpurification.

Step 7. To a solution of D17 (780 mg, 2.12 mmol) in THF (5 mL) and DCM(20 mL) was added PCC (911 mg, 4.24 mmol) at 25° C. The mixture wasstirred at 25° C. for 2 hrs. The solution was filtered and the filtercake was washed with DCM (2×50 mL). The combined filtrate wasconcentrated in vacuum. The residue was purified by silica gel columneluted with (PE/EtOAc=6/1) to afford D18 (340 mg, 40%) as an off-whitesolid.

D18: ¹H NMR (400 MHz, CDCl₃) δ 3.33 (s, 3H), 2.55-2.53 (m, 1H),2.19-2.10 (m, 4H), 2.07-1.88 (m, 3H), 1.81-1.60 (m, 4H), 1.57-1.51 (m,3H), 1.50-1.35 (m, 5H), 1.30-1.07 (m, 10H), 0.60 (s, 3H).

Step 8. To a solution of D18 (340 mg, 0.932 mmol) and HBr (0.1 mL, 48%in water) in MeOH (8 mL) was added drop wise bromine (177 mg, 1.11mmol). The reaction mixture was stirred at 25° C. for 2 hrs. Thereaction was quenched by saturated aqueous NaHCO₃ (20 mL) and the pH wasadjusted to 7-8. The mixture was extracted with EtOAc (2×30 mL), and thecombined organic layers was washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated in vacuum. The residue was purified bysilica gel column eluted with (PE/EtOAc=8/1) to afford D19 (240 mg, 52%)as colorless oil.

D19: ¹H NMR (400 MHz, CDCl₃) δ 3.94-3.86 (m, 2H), 3.32 (s, 3H),2.84-2.79 (m, 1H), 2.23-2.13 (m, 1H), 1.97-1.87 (m, 3H), 1.82-1.67 (m,3H), 1.54-1.35 (m, 7H), 1.31-1.10 (m, 9H), 0.91-0.83 (m, 3H), 0.63 (s,3H).

Step 9. To a solution of D19 (120 mg, 0.27 mmol) in acetone (3 mL) wasadded K₂CO₃ (74.6 mg, 0.54 mmol) and 5-methyl-2H-tetrazole (34 mg, 0.405mmol) at 25° C. The mixture was stirred at 25° C. for 3 hrs. The mixturewas poured into water (30 mL) and extracted with ethyl acetate (2×30mL). The combined organic layers was washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by preparative HPLC to give 73 (23.8 mg, 20%) and 74 (30.3 mg,25%) as an off-white solid.

73: ¹H NMR (400 MHz, CDCl₃) δ 5.34 (s, 2H), 3.33 (s, 3H), 2.65-2.58 (m,1H), 2.56 (s, 3H), 2.27-2.14 (m, 1H), 2.11-2.03 (m, 1H), 1.98-1.87 (m,2H), 1.84-1.69 (m, 3H), 1.67-1.56 (m, 3H), 1.52-1.38 (m, 6H), 1.37-1.09(m, 10H), 0.70 (s, 3H). LCMS Rt=0.954 min in 2.0 min chromatography, MSESI calcd. for C25H₃₇D2N₄O₂ [M+H—H₂O]⁺429, found 429.

74: ¹H NMR (400 MHz, CDCl₃) δ 5.16-5.02 (m, 2H), 3.33 (s, 3H), 2.67-2.63(m, 1H), 2.47 (s, 3H), 2.29-2.14 (m, 1H), 2.10-2.02 (m, 1H), 1.97-1.85(m, 2H), 1.84-1.70 (m, 3H), 1.67-1.57 (m, 3H), 1.49-1.40 (m, 6H),1.38-1.08 (m, 10H), 0.67 (s, 3H). LCMS Rt=0.886 min in 2.0 minchromatography, MS ESI calcd. for C₂₅H₃₇D₂N₄O₂ [M+H—H₂O]⁺429, found 429.

Example 42. Synthesis of Compound 75

To a solution of A1 (200 mg, 453 μmol) in acetone (2 mL) was added5-fluoro-2H-pyrazolo[3,4-c]pyridine (74.4 mg, 543 μmol) and K₂CO₃ (125mg, 906 μmol) at 25° C. The mixture was stirred at 25° C. for 12 hrs,poured into water (10 mL), and extracted with EtOAc (2×20 mL). Thecombined organic solution was washed with brine (10 mL) and dried overNa₂SO₄. The organic layer was filtered and concentrated under reducedpressure to give crude product, which was purified by preparative HPLCto give 75 (17 mg, 7%) as an off-white solid.

75: ¹H NMR (400 MHz, CDCl₃) δ 8.93 (s, 1H), 7.97 (s, 1H), 7.07 (s, 1H),5.35-5.17 (m, 2H), 3.51-3.35 (m, 2H), 3.30 (s, 3H), 2.68 (t, J=8.9 Hz,1H), 2.29-2.00 (m, 3H), 1.80-1.69 (m, 4H), 1.55-1.38 (m, 8H), 1.35-1.09(m, 9H), 1.06-0.83 (m, 2H), 0.73 (s, 3H). LCMS Rt=1.018 min in 1.5 minchromatography, MS ESI calcd. for C₂₉H₄₁FN₃O₃[M+H]⁺ 498, found 498.

Example 43. Synthesis of Compound 76

Step 1. To a solution of E1 (6 g, 19.7 mmol) in toluene (100 mL) wasadded pyridine hydrochloride (453 mg, 3.94 mmol) and ethane-1,2-diol(6.1 g, 98.4 mmol). The mixture was stirred at 130° C. for 16 hrs, thenconcentrated in vacuum. The residue was purified by silica gel columneluted with (PE/EtOAc=5/1) to afford E2 (5.4 g, 66%) as an off-whitesolid.

E2: ¹H NMR (400 MHz, CDCl₃) δ 3.98-3.80 (m, 9H), 3.58-3.55 (m, 1H),2.10-2.01 (m, 1H), 1.99-1.91 (m, 2H), 1.84-1.60 (m, 5H), 1.59-1.33 (m,10H), 1.30-1.17 (m, 4H), 1.15-1.02 (m, 1H), 0.82 (s, 3H).

Step 2. To a solution of E2 (5.3 g, 13.5 mmol) in DCM (60 mL) was addedPCC (4.34 g, 20.2 mmol) at 25° C. The mixture was stirred at 25° C. for30 mins. The solution was filtered and the filtered cake was washed withDCM (2×100 mL). The combined filtrate was washed with saturated NaHCO₃(100 mL) and brine (100 mL), dried over Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by silica gel columneluted with (PE/EtOAc=8/1) to afford E3 (3.1 g, 53%) as a colorless oil.

E3: ¹H NMR (400 MHz, CDCl₃) δ 9.58 (s, 1H), 4.00-3.84 (m, 8H), 2.25-2.15(m, 1H), 2.03-1.88 (m, 2H), 1.84-1.59 (m, 7H), 1.56-1.32 (m, 10H),1.30-1.17 (m, 1H), 1.13-0.99 (m, 1H), 0.92 (s, 3H).

Step 3. To a solution of E3 (3 g, 7.68 mmol) in THF (50 mL) was addedMeMgBr (5.1 mL, 15.3 mmol, 3M in ethyl ether) at 0° C. The mixture wasstirred at 25° C. for 2 hrs. The reaction was poured into water (100 mL)and extracted with EtOAc (2×100 mL). The combined organic layer waswashed with brine (100 mL), dried over Na₂SO₄, filtered and concentratedin vacuum to afford E4 (2.8 g, 81%) as colorless oil.

E4: ¹H NMR (400 MHz, CDCl₃) δ 4.42 (m, 1H), 3.97-3.81 (m, 8H), 2.03-1.92(m, 2H), 1.90-1.74 (m, 5H), 1.71-1.64 (m, 1H), 1.60-1.34 (m, 9H),1.30-1.22 (m, 4H), 1.21-1.11 (m, 5H), 0.87 (s, 3H).

Step 4. To a solution of E4 (2.7 g, 6.64 mmol) in DMF (20 mL) was addedNaH (795 mg, 19.9 mmol, 60%) at 25° C. The mixture was stirred at 50° C.for 30 mins. MeI (2.82 g, 19.9 mmol) was added drop wise to thereaction. The mixture was stirred at 50° C. for 2 hrs, followed byaddition of another aliquot of MeI (2.82 g, 19.9 mmol). The mixture wasstirred at 50° C. for 1 h, then poured into ice water (50 mL) andextracted with EtOAc (2×60 mL). The combined organic phase was washedwith saturated brine (100 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by columnchromatography on silica gel (PE/EtOAc=10/1) to afford E5 (2 g, 64%) asan off-white solid.

E5: ¹H NMR (400 MHz, CDCl₃) δ 3.97-3.83 (m, 8H), 3.79-3.74 (m, 1H), 3.29(s, 3H), 2.08-1.93 (m, 2H), 1.91-1.75 (m, 3H), 1.73-1.57 (m, 3H),1.54-1.36 (m, 8H), 1.31-1.05 (m, 9H), 0.88 (s, 3H).

Step 5. To a solution of E5 (2 g, 4.75 mmol) in THF (30 mL) was addedaq. HCl (4.75 mL, 4M, 19 mmol). The mixture was stirred at 25° C. for 16hrs, then poured into water (100 mL) and extracted with EtOAc (2×50 mL).The combined organic layers were washed with saturated aqueous NaHCO₃(50 mL), brine (50 mL), dried over Na₂SO₄ and concentrated in vacuum toafford E6 (1.4 g, 80%) as an off-white solid.

E6: ¹H NMR (400 MHz, CDCl₃) δ 3.86-3.82 (m, 1H), 3.31 (s, 3H), 2.77-2.67(m, 1H), 2.54-2.43 (m, 1H), 2.32-2.19 (m, 3H), 2.16-1.94 (m, 4H),1.91-1.78 (m, 3H), 1.75-1.60 (m, 4H), 1.55-1.35 (m, 2H), 1.30-1.16 (m,4H), 1.10-1.05 (m, 3H), 0.93 (s, 3H).

Step 6. To a solution of BHT (5.56 g, 25.2 mmol) in toluene (50 mL) wasadded dropwise AlMe₃ (6.3 mL, 12.6 mmol, 2 M in toluene) at 0° C. Themixture was stirred at 25° C. for 1 h. A solution of E6 (1.4 g, 4.21mmol) in toluene (20 mL) was added drop wise to the mixture at −65° C.After stirring at −65° C. for 1 h, MeMgBr (4.19 mL, 12.6 mmol, 3M inethyl ether) was added drop wise at −65° C. The resulting solution wasstirred at −65° C. for 3 hrs. The reaction was quenched by saturatedaqueous NH₄Cl (50 mL) at −65° C. After stirring at 25° C. for 0.5 h, theresulting mixture was filtered through a celite pad and the pad waswashed with EtOAc (100 mL). The combined organic layer was separated,washed with brine (2×100 mL), dried over Na₂SO₄, filtered andconcentrated in vacuum. The crude product was purified by silica gelcolumn eluted with PE/EtOAc=5/1 to give E7 (1.1 g, 68%) as an off-whitesolid.

E7: ¹H NMR (400 MHz, CDCl₃) δ 3.80-3.75 (m, 1H), 3.29 (s, 3H), 2.48-2.41(m, 1H), 2.15-2.02 (m, 1H), 2.00-1.77 (m, 4H), 1.74-1.63 (m, 4H),1.57-1.33 (m, 7H), 1.29-1.13 (m, 9H), 1.08 (d, J=6.4 Hz, 3H), 0.89 (s,3H). LCMS Rt=0.954 min in 2.0 min chromatography, MS ESI calcd. ForC₂₁H₃₁₀ [M+H—H₂O−MeOH]⁺299, found 299.

Step 7. To a solution of PPh₃EtBr (3.18 g, 8.58 mmol) in THF (15 mL) wasadded t-BuOK (962 mg, 8.58 mmol) at 25° C. After stirring at 60° C. for1 h, a solution of E7 (1 g, 2.86 mmol) in THF (5 mL) was added dropwiseat 60° C. The reaction mixture was stirred at 60° C. for 16 hrs, and themixture was poured into ice-water (100 mL) and extracted with EtOAc(2×50 mL). The organic layer was washed with brine (50 mL), dried overNa₂SO₄ and filtered, concentrated in vacuum. The residue was purified bysilica gel column eluted with PE/EtOAc=15/1 to afford E8 (1 g, 78%) asan off-white solid.

E8: ¹H NMR (400 MHz, CDCl₃) δ 5.18-4.99 (m, 1H), 3.83-3.71 (m, 1H), 3.30(s, 3H), 2.45-2.09 (m, 3H), 2.01-1.81 (m, 3H), 1.68-1.58 (m, 6H),1.58-1.37 (m, 7H), 1.31-1.12 (m, 10H), 1.08-1.03 (m, 3H), 0.91 (s, 3H).

Step 8. To a solution of E8 (1 g, 2.77 mmol) in THF (20 mL) was addeddropwise a solution of BH₃-Me₂S (2.77 mL, 27.7 mmol) at 0° C. Thesolution was stirred at 25° C. for 16 hrs. After cooling to 0° C., asolution of NaOH (9.23 mL, 3M) was added very slowly. After the additionwas complete, H₂O₂ (4.5 mL, 33%) was added slowly and the innertemperature was maintained below 10° C. The resulting solution wasstirred at 25° C. for 2 hrs. The resulting solution was extract withEtOAc (2×20 mL), and the combined organic layer was washed withsaturated aqueous Na₂S203 (2×50 mL), brine (50 mL), dried over Na₂SO₄,filtered and concentrated in vacuum to give E9 (0.9 g, crude) as anoff-white solid. The crude product was used for the next step withoutfurther purification.

Step 9. To a solution of E9 (800 mg, 2.11 mmol) in DCM (10 mL) was addedPCC (907 mg, 4.22 mol) at 25° C. The mixture was stirred at 25° C. for 2hrs. The solution was filtered and the filter cake was washed with DCM(2×50 mL). The combined filtrate was concentrated in vacuum. The residuewas purified by silica gel column eluted with (PE/EtOAc=5/1) to afford76 (600 mg, 68%) as a white solid.

76: ¹H NMR (400 MHz, CDCl₃) δ 3.78-3.74 (m, 1H), 3.27 (s, 3H), 2.56-2.51(m, 1H), 2.22-2.16 (m, 1H), 2.12 (s, 3H), 2.06-1.94 (m, 2H), 1.91-1.79(m, 1H), 1.74-1.61 (m, 6H), 1.50-1.32 (m, 6H), 1.29-1.10 (m, 10H), 1.06(d, J=6.0 Hz, 3H), 0.64 (s, 3H). LCMS Rt=1.067 min in 2.0 minchromatography, MS ESI calcd. For C₂₃H₃₅O [M+H—H₂O−MeOH]⁺327, found 327.

Example 44. Synthesis of Compounds 77 and 78

Step 1. To a solution of 76 (300 mg, 0.796 mmol) and HBr (0.1 mL, 48% inwater) in MeOH (5 mL) was added drop wise bromine (190 mg, 1.19 mmol).The reaction mixture was stirred at 25° C. for 2 hrs. The reaction wasquenched by saturated aqueous NaHCO₃ (20 mL) and the pH was adjusted to7-8. The mixture was extracted with EtOAc (2×30 mL), and the combinedorganic layers was washed with brine (50 mL), dried over Na₂SO₄,filtered and concentrated in vacuum. The residue was purified by silicagel column eluted with (PE/EtOAc=8/1) to afford E10 (240 mg, 60%) as anoff-white solid.

E10: ¹H NMR (400 MHz, CDCl₃) δ 3.98-3.86 (m, 2H), 3.77-3.73 (m, 1H),3.26 (s, 3H), 2.85-2.83 (m, 1H), 2.27-2.13 (m, 1H), 2.02-1.83 (m, 3H),1.77-1.61 (m, 5H), 1.54-1.33 (m, 7H), 1.31-1.11 (m, 8H), 1.08-1.02 (m,3H), 0.91-0.80 (m, 2H), 0.67 (s, 3H).

Step 2. To a solution of E10 (120 mg, 0.263 mmol) in acetone (3 mL) wasadded K₂CO₃ (72.5 mg, 0.526 mmol) and 5-methyl-2H-tetrazole (44.2 mg,0.526 mmol) at 25° C. The mixture was stirred at 25° C. for 16 hrs. Themixture was poured into water (30 mL) and extracted with EtOAc (2×30mL). The combined organic layers was washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by preparative HPLC to give 77 (15 mg, 12%) and 78 (32 mg, 27%)as an off-white solid.

77: ¹H NMR (400 MHz, CDCl₃) δ 5.43-5.29 (m, 2H), 3.79-3.74 (m, 1H), 3.27(s, 3H), 2.65-2.60 (m, 1H), 2.57 (s, 3H), 2.30-2.16 (m, 1H), 2.11-2.08(m, 1H), 2.01-1.95 (m, 1H), 1.76-1.65 (m, 1H), 1.80-1.63 (m, 6H),1.52-1.34 (m, 6H), 1.33-1.10 (m, 10H), 1.07 (d, J=6.4 Hz, 3H), 0.74 (s,3H). LCMS Rt=0.990 min in 2.0 min chromatography, MS ESI calcd. forC₂₆H₄₁N₄O₂ [M+H—H₂O]⁺441, found 441.

78: ¹H NMR (400 MHz, CDCl₃) δ 5.21-5.02 (m, 2H), 3.79-3.74 (m, 1H), 3.28(s, 3H), 2.71-2.61 (m, 1H), 2.48 (s, 3H), 2.29-2.17 (m, 1H), 2.09-2.06(m, 1H), 2.03-1.93 (m, 1H), 1.90-1.87 (m, 1H), 1.83-1.62 (m, 6H),1.53-1.41 (m, 6H), 1.39-1.11 (m, 10H), 1.07 (d, J=6.4 Hz, 3H), 0.71 (s,3H). LCMS Rt=0.910 min in 2.0 min chromatography, MS ESI calcd. forC₂₆H₄₁N₄O₂ [M+H—H₂O]⁺441, found 441.

Example 45. Synthesis of Compounds 79 and 80

To a solution of A1 (6 g, 13.5 mmol) in acetone (60 mL) was added K₂CO₃(3.73 g, 27.0 mmol) and ethyl 2H-1,2,3-triazole-4-carboxylate (2.85 g,20.2 mmol). The mixture was stirred at 25° C. for 2 hrs, then filtered.The filtrate was washed with brine (40 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by column chromatography onsilica gel (PE/EtOAc=2/1-1/1) to give 79 (2.26 g, crude) and 80 (2.47 g,crude) as an off-white solid. 100 mg of crude 79 and 80 were purified bypreparative HPLC to give 79 (20 mg) and 80 (20 mg). ¹H NMR (400 MHz,CDCl₃) δ 8.10 (s, 1H), 5.33-5.23 (m, 2H), 4.42 (q, J=7.2 Hz, 2H),3.48-3.36 (m, 2H), 3.28 (s, 3H), 2.61-2.59 (m, 1H), 2.21-0.84 (m, 29H),0.72 (s, 3H). LCMS Rt=1.314 min in 2 min chromatography, 10-80AB; MS ESIcalcd. for C₂₈H₄₃N₃O₅ [M+Na]+524, found 524.

80: ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 5.30-5.14 (m, 2H), 4.43 (q,J=7.2 Hz, 2H), 3.48-3.36 (m, 2H), 3.28 (s, 3H), 2.67-2.60 (m, 1H),2.22-2.00 (m, 4H), 1.75-0.86 (m, 25H), 0.68 (s, 3H). LCMS R_(t)=1.247min in 2 min chromatography, MS ESI calcd. for: C₂₈H₄₄N₃O₅ [M+H]⁺ 502,found 502.

Example 46. Synthesis of Compound 81

To a solution of 79 (4 g, 7.97 mmol) in EtOH/H₂O (30 mL/30 mL) was addedLiOH.H₂O (1.33 g, 31.8 mmol). The mixture was stirred at 25° C. for 2hrs, at which point H₂O (30 mL) was added. The mixture was acidified topH=3 with 2N HCl, followed by removal of EtOH by evaporation. Theaqueous phase was extracted with EtOAc (3×20 mL), and the combinedorganic layer was washed with brine (50 mL), dried over Na₂SO₄, filteredand concentrated to give 81 (3.6 g, crude). 100 mg of crude 81 waspurified by preparative-HPLC to give 81 (21.2 mg, 21%).

81: ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 5.35-5.26 (m, 2H), 3.47-3.36(m, 2H), 3.28 (s, 3H), 2.62-2.60 (m, 1H), 2.20-0.85 (m, 27H), 0.72 (s,3H). LCMS R_(t)=1.185 min in 2 min chromatography, MS ESI calcd. forC26H₃₉N₃O₅Na [M+Na]⁺496, found 496.

Example 47. Synthesis of Compound 82

To a solution of 80 (3.7 g, 7.37 mmol) in EtOH/H₂O (30 mL/30 mL) wasadded lithium hydroxide hydrate (1.23 g, 29.4 mmol). The mixture wasstirred at 25° C. for 2 hrs, at which point H₂O (30 mL) was added. Themixture was acidified to pH=3 with 2N HCl, then EtOH was removed underevaporation. The aqueous layer was extracted with EtOAc (3×50 mL), andthe combined organic layer was washed with brine (100 mL), dried overNa₂SO₄, filtered and concentrated to give 82 (2.34 g, crude). 100 mg ofcrude 82 was purified by preparative HPLC to give 82 (21 mg 21%).

82: ¹H NMR (400 MHz, CDCl₃) δ 8.25 (s, 1H), 5.32-5.17 (m, 2H), 3.48-3.36(m, 2H), 3.29 (s, 3H), 2.68-2.64 (m, 1H), 2.35-2.03 (m, 4H), 1.76-1.40(m, 4H), 1.39-1.28 (m, 8H), 1.25-0.87 (m, 11H), 0.69 (s, 3H). LCMSR_(t)=1.135 min in 2 min chromatography, MS ESI calcd. for C₂₆H₄₀N₃O₅[M+H]⁺ 474, found 474.

Example 48. Synthesis of Compound 83

To a solution of 81 (200 mg, 0.42 mmol) in DCM (20 mL) was added TEA(213 mg, 2.11 mmol) and HATU (240 mg, 0.63 mmol). After stirring for 30mins at 25° C., NH₄Cl (35.7 mg, 0.675 mmol) was added and the mixturewas stirred for another 30 mins. The reaction mixture was washed withwater (2×20 mL) and the organic layer was concentrated in vacuum to give83 (150 mg, crude). 50 mg of crude 83 was purified by preparative HPLCto give 83 (21, 42%).

83: ¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), δ 6.57 (br, 1H), δ 5.50 (br,1H), 5.29-5.17 (m, 2H), 3.49-3.36 (m, 2H), 3.29 (s, 3H), 2.64-2.60 (m,1H), 2.21-2.02 (m, 3H), 1.76-1.40 (m, 4H), 1.39-1.28 (m, 8H), 1.25-0.87(m, 11H), 0.73 (s, 3H). LCMS R_(t)=1.243 min in 2 min chromatography, MSESI calcd. for C26H₄₀N₄O₄Na [M+Na]⁺495, found 495.

Example 49. Synthesis of Compound 84

To a solution of 82 (200 mg, 0.422 mmol) in DCM (20 mL) was added TEA(213 mg, 2.11 mmol) and HATU (240 mg, 0.63 mmol). After stirring 30 minat 25° C., NH₄Cl (35.7 mg, 0.675 mmol) was added and the mixture wasstirred for another 30 min. The reaction mixture was washed with water(2×20 mL) and the organic layer was concentrated under vacuum to give 84(150 mg, crude). 50 mg of crude 84 was purified by preparative HPLC togive 84 (20 mg, 40%).

84: ¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), δ 7.03 (br, 1H), δ 5.59 (br,1H), 5.28-5.12 (mmol, 2H), 3.48-3.36 (m, 2H), 3.29 (s, 3H), 2.67-2.63(m, 1H), 2.27-2.04 (m, 3H), 1.76-1.40 (m, 4H), 1.39-1.28 (m, 8H),1.25-0.87 (m, 11H), 0.69 (s, 3H). LCMS R_(t)=1.201 min in 2 minchromatography, MS ESI calcd. for C₂₆H₃₉N₄O₃ [M+H—H₂O]⁺455, found 455.

Example 50. Synthesis of Compound 85

To a stirred solution of A1 (100 mg, 0.226 mmol) in acetone (10 mL) wasadded K₂CO₃ (62.4 mg, 0.452 mmol) and (1H-1,2,3-triazol-4-yl)methanol(33.5 mg, 0.339 mmol) at 25° C. The reaction mixture was stirred for 2hrs at 25° C., at which point the reaction mixture was filtered, and thefiltrate was concentrated. The residue was purified by preparative HPLCto give 85 (66 mg, 64%) as a white solid.

85: ¹H NMR (400 MHz, CDCl₃) δ 7.65 (s 1H), 5.25-5.14 (m, 2H), 4.80-4.75(m, 2H), 2.61-2.59 (m, 1H), 2.19-2.05 (m, 4H), 1.72-1.40 (m, 16H),1.38-1.05 (m, 10H), 1.04-0.85 (m, 2H), 0.72 (s, 3H). LCMS R_(t)=1.231min in 2 min chromatography, MS ESI calcd. for C₂₆H₄₁N₃O₄Na [M+Na]⁺482,found 482.

Assay Methods

Compounds provided herein can be evaluated using various assays;examples of which are described below.

Steroid Inhibition of TBPS Binding

TBPS binding assays using rat brain cortical membranes in the presenceof 5 μM GABA has been described (Gee et al, J. Pharmacol. Exp. Ther.1987, 241, 346-353; Hawkinson et al, Mol. Pharmacol. 1994, 46, 977-985;Lewin, A. H et al., Mol. Pharmacol. 1989, 35, 189-194).

Briefly, cortices are rapidly removed following decapitation of carbondioxide-anesthetized Sprague-Dawley rats (200-250 g). The cortices arehomogenized in 10 volumes of ice-cold 0.32 M sucrose using aglass/teflon homogenizer and centrifuged at 1500×g for 10 min at 4° C.The resultant supernatants are centrifuged at 10,000×g for 20 min at 4°C. to obtain the P2 pellets. The P2 pellets are resuspended in 200 mMNaCl/50 mM Na—K phosphate pH 7.4 buffer and centrifuged at 10,000×g for10 min at 4° C. This washing procedure is repeated twice and the pelletsare resuspended in 10 volumes of buffer. Aliquots (100 μL) of themembrane suspensions are incubated with 3 nM [³⁵S]-TBPS and 5 μLaliquots of test drug dissolved in dimethyl sulfoxide (DMSO) (final0.5%) in the presence of 5 μM GABA. The incubation is brought to a finalvolume of 1.0 mL with buffer. Nonspecific binding is determined in thepresence of 2 μM unlabeled TBPS and ranged from 15 to 25%. Following a90 min incubation at room temp, the assays are terminated by filtrationthrough glass fiber filters (Schleicher and Schuell No. 32) using a cellharvester (Brandel) and rinsed three times with ice-cold buffer. Filterbound radioactivity is measured by liquid scintillation spectrometry.Non-linear curve fitting of the overall data for each drug averaged foreach concentration is done using Prism (GraphPad). The data are fit to apartial instead of a full inhibition model if the sum of squares issignificantly lower by F-test. Similarly, the data are fit to a twocomponent instead of a one component inhibition model if the sum ofsquares is significantly lower by F-test. The concentration of testcompound producing 50% inhibition (IC₅₀) of specific binding and themaximal extent of inhibition (I_(max)) are determined for the individualexperiments with the same model used for the overall data and then themeans±SEM.s of the individual experiments are calculated. Picrotoxinserves as the positive control for these studies as it has beendemonstrated to robustly inhibit TBPS binding.

Various compounds are or can be screened to determine their potential asmodulators of [³⁵S]-TBPS binding in vitro. These assays are or can beperformed in accordance with the above discussed procedures.

For Table 2, “A” indicates an IC₅₀<10 nM, “B” indicates an IC₅₀ of 10 nMto 50 nM, “C” indicates an IC₅₀ of 50 nM to 100 nM, “D” indicates anIC₅₀ of 100 nM to 500 nM, and “E” indicates IC₅₀>500 nM.

TABLE 2 35S-TBPS Radioligand Displacement Compound (IC₅₀) 1 A 2 A 7 A 8A 9 A 10 A 11 A 12 A 13 A 14 A 15 A 16 A 17 B 18 A 19 A 20 A 21 A 22 D23 A 24 A 25 A 26 A 27 A 28 A 29 A 30 A 34 B 35 E 36 D 37 D 38 C 40 C 41C 42 B 43 C 44 B 45 C 46 B 47 B 48 C 49 C 51 A 52 B 59 D 60 D 61 D 62 B63 D 64 D 65 A 66 B 67 B 68 A 69 A 70 A 71 B 72 A 73 B 74 D 75 D 80 D 81E 82 E 83 D 84 D 85 E

1-66. (canceled)
 67. A method for treating a CNS-related disorder in ahuman subject in need thereof, comprising administering to the humansubject a therapeutically effective amount of (a) a compound of Formula(I) or a pharmaceutically acceptable salt thereof or (b) apharmaceutical composition comprising a compound of Formula (I) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient, wherein:

each X, Y, and Z is independently CH or N; G is —C(R^(3a))(R^(3b))(OR¹);R¹ is C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl; R² is C₁-C₆ alkyl, or C₁-C₆ alkoxy;each of R^(3a) and R^(3b) is independently H, D, or C₁-C₆ alkyl; R^(a)is cyano, halogen, nitro, C₁-C₆ alkyl, C₁-C₆ alkoxy, S(O)_(m)R^(b),NR^(c)R^(d), C(O)R^(e), or C(O)OR^(f); R^(b) is C₁-C₆ alkyl,NR^(c)R^(d), or OR^(f); each of R^(c) and R^(d) is independently H,C₁-C₆ alkyl, C(O)R^(e), or C(O)OR^(f); R^(e) is C₁-C₆ alkyl orNR^(g)R^(h); R^(f) is H or C₁-C₆ alkyl; each of R^(g) and R^(h) isindependently H or C₁-C₆ alkyl; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4;and the compound is not selected from a compound selected from:


68. The method of claim 67, wherein R¹ is C₁-C₆ alkyl.
 69. The method ofclaim 68, wherein R¹ is —CH₃, —CH₂CH₃, or —CH(CH₃)₂.
 70. The method ofclaim 67, wherein R² is C₁-C₆ alkyl.
 71. The method of claim 70, whereinR² is —CH₃.
 72. The method of claim 67, wherein each of R^(3a) andR^(3b) is independently H or D.
 73. The method of claim 67, wherein eachof R^(3a) and R^(3b) is independently H.
 74. The method of claim 67,wherein one of R^(3a) and R^(3b) is H, D, or C₁-C₆ alkyl, and the otherof R^(3a) and R^(3b) is H.
 75. The method of claim 67, wherein thecompound Formula (I) is a compound of Formula (I-a) or (I-b):


76. The method of claim 75, wherein X is N, and Y and Z are CH.
 77. Themethod of claim 75, wherein X and Z are N, and Y is CH.
 78. The methodof claim 75, wherein X, Y, and Z are N.
 79. The method of claim 75,wherein R¹ is C₁-C₆ alkyl.
 80. The method of claim 75, wherein R² isC₁-C₆ alkyl.
 81. The method of claim 75, wherein each of R^(3a) andR^(3b) is independently H or D.
 82. The method of claim 75, wherein oneof R^(3a) and R^(3b) is H, D, or C₁-C₆ alkyl, and the other of R^(3a)and R^(3b) is H.
 83. The method of claim 75, wherein one of R^(3a) andR^(3b) is D or C₁-C₆ alkyl, and the other of R^(3a) and R^(3b) is H. 84.The method of claim 75, wherein n is
 1. 85. The method of claim 75,wherein R^(a) is C₁-C₆ alkyl, or C₁-C₆ alkoxy.
 86. The method of claim75, wherein R^(a) is S(O)_(m)R^(b), NR^(c)R^(d), C(O)R^(e), orC(O)OR^(f).
 87. The method of claim 75, wherein R^(a) is halogen. 88.The method of claim 75, wherein n is 1 or 2, and R^(a) is cyano,halogen, nitro, or C₁-C₆ alkoxy.
 89. The method of claim 67, wherein thecompound is selected from:

and a pharmaceutically acceptable salt thereof.
 90. The method of claim67, wherein the CNS-related disorder is a sleep disorder, a mooddisorder, a schizophrenia spectrum disorder, a convulsive disorder, adisorder of memory and/or cognition, a movement disorder, a personalitydisorder, autism spectrum disorder, pain, traumatic brain injury, avascular disease, a substance abuse disorder and/or withdrawal syndrome,or tinnitus.
 91. The method of claim 90, wherein the CNS-relateddisorder is a mood disorder.
 92. The method of claim 91, wherein themood disorder is depression.
 93. The method of claim 92, wherein thedepression is postnatal depression.